ORCID Profile
0000-0002-7388-3612
Current Organisation
QIMR Berghofer Medical Research Institute
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Animal Physiology - Systems | Allergy | Immunology | Innate Immunity
ANZSRC Socio-Economic Objective (SEO)
Respiratory System and Diseases (incl. Asthma) | Immune System and Allergy | Expanding Knowledge in the Medical and Health Sciences |
Related Links
Publications
Sensorimotor circuitry involved in the higher brain control of coughing
Publisher: Springer Science and Business Media LLC
Date: 2013
Human Metapneumovirus Impairs Apoptosis of Nasal Epithelial Cells in Asthma via HSP70
Publisher: S. Karger AG
Date: 11-10-2017
DOI: 10.1159/000449101
Abstract: Asthmatics are highly susceptible to respiratory viral infections, possibly due to impaired innate immunity. However, the exact mechanisms of susceptibility are likely to differ amongst viruses. Therefore, we infected primary nasal epithelial cells (NECs) from adults with mild-to-moderate asthma, with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in vitro and investigated the antiviral response. NECs from these asthmatics supported elevated hMPV but not RSV infection, compared to non-asthmatic controls. This correlated with reduced apoptosis and reduced activation of caspase-9 and caspase-3/7 in response to hMPV, but not RSV. The expression of heat shock protein 70 (HSP70), a known inhibitor of caspase activation and subsequent apoptosis, was lified in response to hMPV infection. Chemical inhibition of HSP70 function restored caspase activation and reduced hMPV infection in NECs from asthmatic subjects. There was no impairment in the production of IFN by NECs from asthmatics in response to either hMPV or RSV, demonstrating that increased infection of asthmatic airway cells by hMPV is IFN-independent. This study demonstrates, for the first time, a mechanism for elevated hMPV infection in airway epithelial cells from adult asthmatics and identifies HSP70 as a potential target for antiviral and asthma therapies.
LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE
Publisher: American Physiological Society
Date: 10-2021
DOI: 10.1152/AJPLUNG.00138.2021
Abstract: The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also h ers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.
IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma
Publisher: Elsevier BV
Date: 10-2023
The effect of hyperpolarization‐activated cyclic nucleotide‐gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone
Publisher: Wiley
Date: 17-07-2014
DOI: 10.1111/BPH.12745
Differential Regulation of Human Eosinophil IL-3, IL-5, and GM-CSF Receptor α-Chain Expression by Cytokines: IL-3, IL-5, and GM-CSF Down-Regulate IL-5 Receptor α Expression with Loss of IL-5 Responsiv
Publisher: The American Association of Immunologists
Date: 06-2003
DOI: 10.4049/JIMMUNOL.170.11.5359
Abstract: Our recent data suggested that tissue eosinophils may be relatively insensitive to anti-IL-5 treatment. We examined cross-regulation and functional consequences of modulation of eosinophil cytokine receptor expression by IL-3, IL-5 GM-CSF, and eotaxin. Incubation of eosinophils with IL-3, IL-5, or GM-CSF led to reduced expression of IL-5Rα, which was sustained for up to 5 days. Eosinophils incubated with IL-5 or IL-3 showed diminished respiratory burst and mitogen-activated protein kinase kinase phosphorylation in response to further IL-5 stimulation. In contrast to these findings, eosinophil expression of IL-3Rα was increased by IL-3, IL-5, and GM-CSF, whereas GM-CSF receptor α was down-regulated by GM-CSF, but was not affected by IL-3 or IL-5. CCR3 expression was down-regulated by IL-3 and was transiently reduced by IL-5 and GM-CSF, but rapidly returned toward baseline. Eotaxin had no effect on receptor expression for IL-3, IL-5, or GM-CSF. Up-regulation of IL-3Rα by cytokines was prevented by a phosphoinositol 3-kinase inhibitor, whereas this and other signaling inhibitors had no effect on IL-5Rα down-regulation. These data suggest dynamic and differential regulation of eosinophil receptors for IL-3, IL-5, and GM-CSF by the cytokine ligands. Since these cytokines are thought to be involved in eosinophil development and mobilization from the bone marrow and are present at sites of allergic inflammation, tissue eosinophils may have reduced IL-5R expression and responsiveness, and this may explain the disappointing effect of anti-IL-5 therapy in reducing airway eosinophilia in asthma.
Microarray Analysis of Eosinophils Reveals a Number of Candidate Survival and Apoptosis Genes
Publisher: American Thoracic Society
Date: 10-2001
Abstract: The increase in eosinophils at the site of antigen challenge has been used as evidence to suggest that this cell type plays a role in the pathophysiology of asthma. Aberrant production of several different cytokines, particularly interleukin (IL)-5, has been shown to result in eosinophilia. IL-5 influences the development and maturation of eosinophils in a number of different ways. Of note is the ability of IL-5 to act as a survival factor for eosinophils specifically inhibiting apoptosis. The precise mechanism by which IL-5 exerts its effect remains obscure. We used microarray technologies to investigate the changes in the messenger RNA expression profile of eosinophils after treatment with IL-5. Using the Affymetrix Hu6800 chip, a total of 80 genes were observed to be regulated by 2-fold or greater. Many of the genes previously identified as regulated by IL-5 were regulated in our microarray experiments. Of the 73 genes found to be upregulated, many were shown to play a role in adhesion, migration, activation, or survival of eosinophils or hematopoietic cells, whereas the function of others was unknown. To facilitate the identification of genes that govern the apoptosis and survivability of eosinophils, we used an alternative cellular model, TF1.8 cells, whose survival was also dependent on IL-5. Comparison of these models identified four genes, Pim-1, DSP-5 (hVH3, B23), CD24, and SLP-76, whose regulation was similarly coordinated in both systems. Identification of Pim-1 and SLP-76 as regulated by IL-5 led us to suggest a direct role for these proteins in the IL-5 signaling pathway in eosinophils. The tissue distribution of these genes demonstrated that Pim-1 and SLP-76 were relatively restricted to the eosinophil compared with their expression in brain, bone marrow, kidney, liver, and lung. By contrast, DSP-5 and CD24 were confirmed as ubiquitous in their expression by microarray.
Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JACI.2009.10.018
Abstract: Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant T(H)2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma. To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life. Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls. Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific T(H)2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, T(H)2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4(+) T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter. Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life.
RAGE and TLRs: Relatives, friends or neighbours?
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.MOLIMM.2013.07.008
Abstract: The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE-TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense.
RSV Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells
Publisher: American Thoracic Society
Date: 06-2020
IRF-3, IRF-7, and IPS-1 Promote Host Defense against Acute Human Metapneumovirus Infection in Neonatal Mice
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.AJPATH.2014.02.026
Abstract: Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-β promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1(-/-) > IRF3/7(-/-) > IRF3(-/-), but not IRF7(-/-), mice compared with wild-type mice. IFN-β and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7(-/-) mice at 5 days after infection. IRF7(-/-) and IRF3/7(-/-) mice presented with airway eosinophilia, whereas only IRF3/7(-/-) mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1(-/-) mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-β, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/β response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.
Intravenous Anti-IL-5 Monoclonal Antibody Reduces Eosinophils and Tenascin Deposition in Allergen-Challenged Human Atopic Skin
Publisher: Elsevier BV
Date: 06-2004
A role for eosinophils in airway remodelling in asthma
Publisher: Elsevier BV
Date: 09-2004
Antigen-specific T-cell responses to a recombinant fowlpox virus are dependent on MyD88 and interleukin-18 and independent of toll-like receptor 7 (TLR7)- and TLR9-mediated innate immune recognition
Publisher: American Society for Microbiology
Date: 04-2011
DOI: 10.1128/JVI.02000-10
Abstract: Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV OVA ), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro , only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV OVA in vivo . The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.
Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus
Publisher: American Society of Hematology
Date: 09-2007
DOI: 10.1182/BLOOD-2007-01-071340
Abstract: Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssRNA) stimulation of the TLR-7–MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF)–7 and eosinophil-associated ribonucleases EAR-1 and EAR-2. Hypereosinophilia in the airways of infected mice also correlated with increased expression of IRF-7, IFN-β, and NOS-2, and inhibition of NO production with the NOS-2 inhibitor L-NMA partially reversed the accelerated virus clearance promoted by eosinophils. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.
Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.PHARMTHERA.2009.06.004
Abstract: Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. Little is known about the mechanisms leading to neutrophilic bronchitis and few treatments are effective in reducing neutrophil accumulation in the airways. There is a similar pattern of inflammatory mediator release and toll like receptor 2 expression in asthma, COPD and bronchiectasis. We propose the existence of an active lification mechanism, an effector arm of the innate immune system, involving toll like receptor 2, operating in persistent neutrophilic bronchitis. Neutrophil persistence in the airways can occur through a number of mechanisms such as impaired apoptosis, efferocytosis and mucus hypersecretion, all of which are impaired in airways disease. Impairment of neutrophil clearance results in a reduced ability to respond to bacterial infection. Persistent activation of airway neutrophils may result in the persistent activation of the innate immune system resulting in further airway insult. Current therapies are limited for the treatment of neutrophilic bronchitis possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.
Anterograde neuronal circuit tracing using a genetically modified herpes simplex virus expressing EGFP
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JNEUMETH.2012.05.035
Abstract: Insights into the anatomical organization of complex neural circuits provide important information about function, and thus tools that facilitate neuroanatomical studies have proved invaluable in neuroscience. Advances in molecular cloning have allowed the production of novel recombinant neuroinvasive viruses for use in transynaptic neural tracing studies. However, the vast majority of these viruses have motility in the retrograde direction only, therefore limiting their use to studies of synaptic input circuitry. Here we describe the construction of an EGFP reporting herpes simplex virus, strain H129, which preferentially moves along synaptically connected neurons in the anterograde direction. In vitro and in vivo characterization studies confirm that the HSV-1 H129-EGFP retains comparable replication and neuroinvasiveness as the wildtype H129 virus. As a proof of principle we confirm anterograde movement of the H129-EGFP along polysynaptic pathways by inoculating the upper airways and tracking time-dependent EGFP expression in previously described ascending sensory pathways. These data confirm a genomic locus for recombining HSV-1 H129 such that normal viral function and replication is maintained. Novel viral recombinants such as HSV-1 H129-EGFP will be useful tools for delineating the central organization of peripheral sensory pathways as well as the synaptic outputs from central neuronal populations.
RAGE: A new frontier in chronic airways disease
Publisher: Wiley
Date: 19-10-2012
Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41421-021-00279-W
Abstract: Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants
Publisher: eLife Sciences Publications, Ltd
Date: 16-02-2021
DOI: 10.7554/ELIFE.61803
Abstract: Influenza virus has a high mutation rate, such that within one host different viral variants can emerge. Evidence suggests that influenza virus variants are more prevalent in pregnant and/or obese in iduals due to their impaired interferon response. We have recently shown that the non-allergic, paucigranulocytic subtype of asthma is associated with impaired type I interferon production. Here, we seek to address if this is associated with an increased emergence of influenza virus variants. Compared to controls, mice with paucigranulocytic asthma had increased disease severity and an increased emergence of influenza virus variants. Specifically, PB1 mutations exclusively detected in asthmatic mice were associated with increased polymerase activity. Furthermore, asthmatic host-derived virus led to increased disease severity in wild-type mice. Taken together, these data suggest that at least a subset of patients with asthma may be more susceptible to severe influenza and may be a possible source of new influenza virus variants.
NK Cell Deficiency Predisposes to Viral-Induced Th2-Type Allergic Inflammation via Epithelial-Derived IL-25
Publisher: The American Association of Immunologists
Date: 15-10-2010
Abstract: Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-γ production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma.
Evaluating vaccinia virus cytokine co‐expression in TLR GKO mice
Publisher: Wiley
Date: 21-12-2010
DOI: 10.1038/ICB.2010.157
Abstract: Using Toll-like receptor (TLR) and MyD88 gene knock-out (GKO) mice the effect of TLRs and MyD88 on virus replication, interferon (IFN)-β production, natural killer (NK) cell and CD8T cell responses were assessed following ectromelia virus (ECTV) and recombinant vaccinia virus (rVV) infection. The capacity for rVVs encoding cytokines to restore immune function in MyD88(-/-) mice was clearly demonstrated. Results showed that TLR2(-/-), TLR4(-/-)and TLR7(-/-) mice survived ECTV infection whereas MyD88(-/-) and TLR9(-/-)mice, in contrast, were highly susceptible. Next, following infection with rVV, MyD88(-/-) mice elicited reduced serum IFN-β, NK cell and CD8T cell responses compared with wild-type mice, whereas TLR9(-/-) mice showed elevated CD8T cell responses. When MyD88(-/-)mice were infected with rVV co-expressing IFN-β these mice were able to restore IFN-β levels and CD8T cell responses but not NK cell activation. Interestingly, even though rVV co-expressing interleukin (IL)-2 enhanced NK cell activation in MyD88(-/-) mice, this was not associated with an antiviral effect, as observed in normal mice. Surprisingly, co-infection with rVV IL-2/rVV IL-12, but not rVV IL-2/rVV IFN-β, restored the attenuated phenotype of rVV IL-2 in MyD88(-/-) mice indicating that the IL-2/IL-12 combination promotes antiviral responses. Our results clearly show that the CD8T cell defect observed in MyD88(-/-) mice to vaccinia virus infection can be restored by rVV-encoding IFN-β demonstrating the critical role of this cytokine in T cell mediated immunity and illustrates that the model can provide an effective platform for the elucidation of cytokine immunobiology.
The Relationship Between Allergen-Induced Tissue Eosinophilia and Markers of Repair and Remodeling in Human Atopic Skin
Publisher: The American Association of Immunologists
Date: 15-10-2002
DOI: 10.4049/JIMMUNOL.169.8.4604
Abstract: Several in vitro studies suggest that eosinophils may play a role in fibrosis, remodeling, and repair processes associated with IgE-mediated hypersensitivity. However, the relationship in vivo, between allergen-induced tissue eosinophilia and markers of repair has yet to be established in human atopic subjects. Using the allergen-induced cutaneous late-phase reaction as a model of allergic inflammation, we have tested the hypothesis that eosinophil-derived TGF-β1 and IL-13 are temporarily associated with myofibroblast formation and deposition of tenascin and procollagen I. Biopsies were taken from atopic volunteers at 1, 3, 6, 24, 48, and 72 h after intradermal allergen challenge and were examined by immunohistochemistry. Following the peak of the late-phase reaction (6 h) there were persisting TGF-β1+ eosinophils, α-smooth muscle actin+ myofibroblasts, tenascin immunoreactivity, and procollagen-I+ cells 24–48 h postchallenge. Direct evidence of generation of repair markers was obtained by coculture of eosinophils and fibroblasts. This resulted in α-smooth muscle actin immunoreactivity that was inhibitable by neutralizing Abs to TGF-β as well as production of tenascin transcripts and protein product. TGF-β1 and IL-13 also induced tenascin expression. We conclude that TGF-β1 and IL-13, provided partially by eosinophils, contribute to repair and remodeling events in allergic inflammation in human atopic skin.
Targeting the P2Y
Publisher: American Thoracic Society
Date: 02-2022
TLR7 Is Involved in Sequence-Specific Sensing of Single-Stranded RNAs in Human Macrophages
Publisher: The American Association of Immunologists
Date: 15-02-2008
DOI: 10.4049/JIMMUNOL.180.4.2117
Abstract: Human TLR7 and 8 (hTLR7/8) have been implicated in the sequence-dependent detection of RNA oligonucleotides in immune cells. Although hTLR7 sequence-specific sensing of short RNAs has been inferred from studies of murine TLR7, this has yet to be established for hTLR7. We found that different short ssRNA sequences selectively induced either TNF-α or IFN-α in human PBMCs. The sequence-specific TNF-α response to ssRNAs observed in PBMCs could be replicated in activated human macrophage-like (THP-1) cells pretreated with IFN-γ. Surprisingly, suppression of hTLR7 expression by RNA interference in this model reduced sensing of all immunostimulatory ssRNAs tested. Modulation of the relative expression ratio of hTLR7 to hTLR8 in THP-1 cells correlated with differential sensing of immunostimulatory sequences. Furthermore, the sequence-specific IFN-α induction profile in human PBMCs was accurately modeled by a sequence-specific activation of murine TLR7 in mouse macrophages. Thus, we demonstrate for the first time that hTLR7 is involved in sequence-specific sensing of ssRNAs. We establish a novel cell model for the prediction of TNF-α induction by short RNAs in human macrophages. Our results suggest that differential sequence-specific sensing of RNA oligonucleotides between human and mouse macrophages is due to the modulation of TLR7 sensing by human TLR8.
Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.JACI.2013.02.041
Abstract: Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood. We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen. TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/β(low), IL-12p70(low), IL-1β(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7. TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
The Influence of the Microbiome on Early-Life Severe Viral Lower Respiratory Infections and Asthma—Food for Thought?
Publisher: Frontiers Media SA
Date: 16-02-2017
Eosinophil trafficking in allergy and asthma
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.JACI.2007.03.048
Abstract: Blood eosinophilia and tissue eosinophilia are characteristic features of allergic inflammation and asthma, conditions associated with prominent production of T(H)2 cytokines IL-4, IL-5, and IL-13. In this review, we will consider recent advances in our understanding of the molecular mechanisms that promote expansion and differentiation of eosinophil progenitors in bone marrow, eosinophil recruitment in response to chemokine receptor 3 agonists eosinophil transit mediated by specific ligand-receptor interactions, and prolonged survival of eosinophils in peripheral tissues. Novel rational therapies including antiselectin and antichemokine receptor modalities designed to block eosinophil development and trafficking are discussed, together with the implications of recent clinical studies that have evaluated the efficacy of humanized anti-IL-5 mAb therapy.
TLR2, but not TLR4, is required for effective host defence against Chlamydia respiratory tract infection in early life.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2012
Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation
Publisher: The American Association of Immunologists
Date: 05-2015
Abstract: Inducible BALT (iBALT) can lify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.
Coinfection with Blood-Stage Plasmodium Promotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung.
Publisher: American Society for Microbiology
Date: 25-02-2015
DOI: 10.1128/CVI.00051-15
Abstract: Acute lower respiratory tract infections (ALRTI) are the leading cause of global childhood mortality, with human respiratory syncytial virus (hRSV) being a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodium infection. Although the incidence of malaria in this region has decreased in recent years, there remains a significant opportunity for coinfection. Recent data show that febrile young children infected with Plasmodium are often concurrently infected with respiratory viral pathogens but are less likely to suffer from pneumonia than are non- Plasmodium -infected children. Here, we hypothesized that blood-stage Plasmodium infection modulates pulmonary inflammatory responses to a viral pathogen but does not aid its control in the lung. To test this, we established a novel coinfection model in which mice were simultaneously infected with pneumovirus of mice (PVM) (to model hRSV) and blood-stage Plasmodium chabaudi chabaudi AS ( Pc AS) parasites. We found that Pc AS infection was unaffected by coinfection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses, and immune cell recruitment to the airways were substantially reduced by coinfection with Pc AS. Importantly, Pc AS coinfection facilitated greater viral dissemination throughout the lung. Although Plasmodium coinfection induced low levels of systemic interleukin-10 (IL-10), this regulatory cytokine played no role in the modulation of lung inflammation or viral dissemination. Instead, we found that Plasmodium coinfection drove an early systemic beta interferon (IFN-β) response. Therefore, we propose that blood-stage Plasmodium coinfection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating type I IFN-dependent responses to respiratory viruses.
Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans
Publisher: Wiley
Date: 09-07-2004
Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma
Publisher: The American Association of Immunologists
Date: 15-06-2012
Abstract: Human rhinoviruses (RV) cause only minor illness in healthy in iduals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy in iduals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p & 0.01), and IL-13 (p & 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.
Evidence that opioids may have toll-like receptor 4 and MD-2 effects
Publisher: Elsevier BV
Date: 2010
RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma
Publisher: eLife Sciences Publications, Ltd
Date: 18-01-2017
DOI: 10.7554/ELIFE.21199
Abstract: Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of in iduals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Publisher: Springer Science and Business Media LLC
Date: 13-05-2015
The Absence of Interferon-β Promotor Stimulator-1 (IPS-1) Predisposes to Bronchiolitis and Asthma-like Pathology in Response to Pneumoviral Infection in Mice
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/S41598-017-02564-9
Abstract: Respiratory syncytial virus (RSV)-bronchiolitis is a major cause of infant morbidity and mortality and a risk factor for subsequent asthma. We showed previously that toll-like receptor (TLR)7 in plasmacytoid dendritic cells (pDCs) is critical for protection against bronchiolitis and asthma in mice infected with pneumonia virus of mice (PVM), the mouse homolog of RSV. This lack of redundancy was unexpected as interferon-β promotor stimulator-1 (IPS-1) signalling, downstream of RIG-I-like receptor (RLR) and not TLR7 activation, contributes to host defence in hRSV-inoculated adult mice. To further clarify the role of IPS-1 signalling, we inoculated IPS-1 −/− and WT mice with PVM in early-life, and again in later-life, to model the association between bronchiolitis and asthma. IPS-1 deficiency predisposed to severe PVM bronchiolitis, characterised by neutrophilic inflammation and necroptotic airway epithelial cell death, high mobility group box 1 (HMGB1) and IL-33 release, and downstream type-2 inflammation. Secondary infection induced an eosinophilic asthma-like pathophysiology in IPS-1 −/− but not WT mice. Mechanistically, we identified that IPS-1 is necessary for pDC recruitment, IFN-α production and viral control. Our findings suggest that TLR7 and RLR signalling work collaboratively to optimally control the host response to pneumovirus infection thereby protecting against viral bronchiolitis and subsequent asthma.
Geometrogenesis under quantum graphity: Problems with the ripening universe
Publisher: American Physical Society (APS)
Date: 02-10-2015
Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JACI.2017.07.051
Abstract: Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs). Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. Anti-IL-33 decreased type 2 inflammation in all phases of disease however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.
Asthma is associated with multiple alterations in anti-viral innate signalling pathways
Publisher: Public Library of Science (PLoS)
Date: 09-09-2014
Antagonism of microRNA-126 suppresses the effector function of T H 2 cells and the development of allergic airways disease
Publisher: Proceedings of the National Academy of Sciences
Date: 03-11-2009
Abstract: Allergic asthma is an inflammatory disease of the lung characterized by abnormal T helper-2 (T H 2) lymphocyte responses to inhaled antigens. The molecular mechanisms leading to the generation of T H 2 responses remain unclear, although toll-like receptors (TLRs) present on innate immune cells play a pivotal role in sensing molecular patterns and in programming adaptive T cell responses. Here we show that in vivo activation of TLR4 by house dust mite antigens leads to the induction of allergic disease, a process that is associated with expression of a unique subset of small, noncoding microRNAs. Selective blockade of microRNA (miR)-126 suppressed the asthmatic phenotype, resulting in diminished T H 2 responses, inflammation, airways hyperresponsiveness, eosinophil recruitment, and mucus hypersecretion. miR-126 blockade resulted in augmented expression of POU domain class 2 associating factor 1, which activates the transcription factor PU.1 that alters T H 2 cell function via negative regulation of GATA3 expression. In summary, this study presents a functional connection between miRNA expression and asthma pathogenesis, and our data suggest that targeting miRNA in the airways may lead to anti-inflammatory treatments for allergic asthma.
Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.JACI.2013.12.1035
Abstract: The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to lify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention.
IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma
Publisher: Cold Spring Harbor Laboratory
Date: 08-11-2022
DOI: 10.1101/2022.11.07.515526
Abstract: Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations, however the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1) and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterized by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI ( Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis, and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal s les from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.
Interleukin-22 suppresses major histocompatibility complex II in mucosal epithelial cells
Publisher: Rockefeller University Press
Date: 11-09-2023
DOI: 10.1084/JEM.20230106
Eosinophils: Biological Properties and Role in Health and Disease
Publisher: Wiley
Date: 25-07-2008
Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway
Publisher: The American Association of Immunologists
Date: 15-05-2011
Abstract: Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8+ T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet–unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.
HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling
Publisher: Public Library of Science (PLoS)
Date: 13-07-2020
The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis
Publisher: MDPI AG
Date: 27-07-2020
DOI: 10.3390/V12080808
Abstract: Acute viral bronchiolitis causes significant mortality in the developing world, is the number one cause of infant hospitalisation in the developed world, and is associated with the later development of chronic lung diseases such as asthma. A vaccine against respiratory syncytial virus (RSV), the leading cause of viral bronchiolitis in infancy, remains elusive, and hence new therapeutic modalities are needed to limit disease severity. However, much remains unknown about the underlying pathogenic mechanisms. Neutrophilic inflammation is the predominant phenotype observed in infants with both mild and severe disease, however, a clear understanding of the beneficial and deleterious effects of neutrophils is lacking. In this review, we describe the multifaceted roles of neutrophils in host defence and antiviral immunity, consider their contribution to bronchiolitis pathogenesis, and discuss whether new approaches that target neutrophil effector functions will be suitable for treating severe RSV bronchiolitis.
Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity
Publisher: The American Association of Immunologists
Date: 15-02-2008
DOI: 10.4049/JIMMUNOL.180.4.2225
Abstract: There is strong epidemiological evidence that Chlamydia infection can lead to exacerbation of asthma. However, the mechanism(s) whereby chlamydial infection, which normally elicits a strong Th type 1 (Th1) immune response, can exacerbate asthma, a disease characterized by dominant Th type 2 (Th2) immune responses, remains unclear. In the present study, we show that Chlamydia muridarum infection of murine bone marrow-derived dendritic cells (BMDC) modulates the phenotype, cytokine secretion profile, and Ag-presenting capability of these BMDC. Chlamydia-infected BMDC express lower levels of CD80 and increased CD86 compared with noninfected BMDC. When infected with Chlamydia, BMDC secrete increased TNF-α, IL-6, IL-10, IL-12, and IL-13. OVA peptide-pulsed infected BMDC induced significant proliferation of transgenic CD4+ DO11.10 (D10) T cells, strongly inhibited IFN-γ secretion by D10 cells, and promoted a Th2 phenotype. Intratracheal transfer of infected, but not control noninfected, OVA peptide-pulsed BMDC to naive BALB/c mice, which had been i.v. infused with naive D10 T cells, resulted in increased levels of IL-10 and IL-13 in bronchoalveolar lavage fluid. Recipients of these infected BMDC showed significant increases in airways resistance and decreased airways compliance compared with mice that had received noninfected BMDC, indicative of the development of airways hyperreactivity. Collectively, these data suggest that Chlamydia infection of DCs allows the pathogen to deviate the induced immune response from a protective Th1 to a nonprotective Th2 response that could permit ongoing chronic infection. In the setting of allergic airways inflammation, this infection may then contribute to exacerbation of the asthmatic phenotype.
Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation
Publisher: American Society for Clinical Investigation
Date: 02-06-2017
The maternal gut microbiome during pregnancy and offspring allergy and asthma
Publisher: Elsevier BV
Date: 09-2021
Allergic sensitization is enhanced in early life through toll‐like receptor 7 activation
Publisher: Wiley
Date: 13-11-2009
DOI: 10.1111/J.1365-2222.2009.03335.X
Abstract: Prospective cohort studies suggest that children hospitalized in early life with severe infections are significantly more likely to develop recurrent wheezing and asthma. Using an inhalational mouse model of allergic airways inflammation, we sought to determine the effect of viral and bacterial-associated molecular patterns on the magnitude of the allergic inflammatory response and whether this effect was age dependent. BALB/c mice were sensitized by intranasal administration of endotoxin(low) ovalbumin (OVA) in the absence or presence of viral single-stranded (ss)RNA, lipoteichoic acid or flagellin as neonates (within the first 24 h of life) or as weanlings (4 weeks of age). Mice were challenged four times with OVA at 6 weeks of age and end-points (bronchoalveolar lavage cytology, histology, antigen-specific T and B cell responses) determined at 7 weeks of age. Inhalational sensitization (<24 h or 4 weeks of age) and challenge with OVA induced a mild allergic inflammatory response in the airways as indicated by increased numbers of eosinophils and mucus cells, elevated serum OVA-specific IgG1, and production of T helper 2 (Th2) cytokines. Mice sensitized to endotoxin(low) OVA at birth in the presence of ssRNA or lipoteichoic acid, but not flagellin, showed an increase in the numbers of airway and tissue eosinophils, mucus producing cells and antigen-specific production of IL-13 as compared with mice exposed only to endotoxin(low) OVA. By contrast, all three TLR ligands failed to increase the magnitude of OVA-induced allergic inflammation in mice sensitized as weanlings. Recognition of distinct microbial-associated patterns in early life may preferentially promote the de novo differentiation of bystander, antigen-specific CD4(+) T cells toward a Th2 phenotype, and promote an asthma-like phenotype upon cognate antigen exposure in later life.
The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1016/S0968-0896(00)00331-X
Abstract: RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.
DP1 prostanoid receptor activation increases the severity of an acute lower respiratory viral infection in mice via TNF-α-induced immunopathology
Publisher: Elsevier BV
Date: 07-2021
A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JCONREL.2019.03.027
Abstract: In a low inflammatory skin environment, Langerhans cells (LCs) - but not dermal dendritic cells (dDCs) - contribute to the pivotal process of tolerance induction. Thus LCs are a target for specific-tolerance therapies. LCs reside just below the stratum corneum, within the skin's viable epidermis. One way to precisely deliver immunotherapies to LCs while remaining minimally invasive is with a skin delivery device such as a microprojection arrays (MPA). Today's MPAs currently achieve rapid delivery (e.g. within minutes of application), but are focussed primarily at delivery of therapeutics to the dermis, deeper within the skin. Indeed, no MPA currently delivers specifically to the epidermal LCs of mouse skin. Without any convenient, pre-clinical device available, advancement of LC-targeted therapies has been limited. In this study, we designed and tested a novel MPA that delivers ovalbumin to the mouse epidermis (eMPA) while maintaining a low, local inflammatory response (as defined by low erythema after 24 h). In comparison to available dermal-targeted MPAs (dMPA), only eMPAs with larger projection tip surface areas achieved shallow epidermal penetration at a low application energy. The eMPA characterised here induced significantly less erythema after 24 h (p = 0.0004), less epidermal swelling after 72 h (p < 0.0001) and 52% less epidermal cell death than the dMPA. Despite these differences in skin inflammation, the eMPA and dMPA promoted similar levels of LC migration out of the skin. However, only the eMPA promoted LCs to migrate with a low MHC II expression and in the absence of dDC migration. Implementing this more mouse-appropriate and low-inflammatory eMPA device to deliver potential immunotherapeutics could improve the practicality and cell-specific targeting of such therapeutics in the pre-clinical stage. Leading to more opportunities for LC-targeted therapeutics such as for allergy immunotherapy and asthma.
PAG1 limits allergen‐induced type 2 inflammation in the murine lung
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/ALL.13991
Abstract: Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Pag1 ‐deficient ( Pag1 −/− ) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1 −/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (T H 2)‐cell differentiation. CD4 + T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4 + T cells to WT or Pag1 −/− recipients demonstrated that the heightened propensity for T H 2‐cell differentiation was both T cell intrinsic and extrinsic. PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and T H 2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.
RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD
Publisher: Wiley
Date: 15-10-2020
DOI: 10.1111/ALL.14563
Abstract: The receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. We measured airway inflammation and AHR in wild‐type, RAGE −/− , TLR4 −/− and TLR4 −/− RAGE −/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. RAGE −/− mice were protected against CS‐induced neutrophilia and AHR. In contrast, TLR4 −/− mice were not protected against CS‐induced neutrophilia and had more severe CS‐induced AHR. TLR4 −/− RAGE −/− mice were not protected against CS‐induced neutrophilia but were partially protected against CS‐induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-05-2018
DOI: 10.1126/SCITRANSLMED.AAO0052
Abstract: Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal s les from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.
Pulmonary Eosinophils and Their Role in Immunopathologic Responses to Formalin-Inactivated Pneumonia Virus of Mice
Publisher: The American Association of Immunologists
Date: 07-2009
Abstract: Enhanced disease is the term used to describe the aberrant Th2-skewed responses to naturally acquired human respiratory syncytial virus (hRSV) infection observed in in iduals vaccinated with formalin-inactivated viral Ags. Here we explore this paradigm with pneumonia virus of mice (PVM), a pathogen that faithfully reproduces features of severe hRSV infection in a rodent host. We demonstrate that PVM infection in mice vaccinated with formalin-inactivated Ags from PVM-infected cells (PVM Ags) yields Th2-skewed hypersensitivity, analogous to that observed in response to hRSV. Specifically, we detect elevated levels of IL-4, IL-5, IL-13, and eosinophils in bronchoalveolar lavage fluid of PVM-infected mice that were vaccinated with PVM Ags, but not among mice vaccinated with formalin-inactivated Ags from uninfected cells (control Ags). Interestingly, infection in PVM Ag-vaccinated mice was associated with a ∼10-fold reduction in lung virus titer and protection against weight loss when compared with infected mice vaccinated with control Ags, despite the absence of serum-neutralizing Abs. Given recent findings documenting a role for eosinophils in promoting clearance of hRSV in vivo, we explored the role of eosinophils in altering the pathogenesis of disease with eosinophil-deficient mice. We found that eosinophil deficiency had no impact on virus titer in PVM Ag-vaccinated mice, nor on weight loss or levels of CCL11 (eotaxin-1), IFN-γ, IL-5, or IL-13 in bronchoalveolar lavage fluid. However, levels of both IL-4 and CCL3 (macrophage inflammatory protein-1α) in bronchoalveolar lavage fluid were markedly diminished in PVM Ag-vaccinated, PVM-infected eosinophil-deficient mice when compared with wild-type controls.
Elevated expression of the NLRP3 inflammasome in neutrophilic asthma
Publisher: European Respiratory Society (ERS)
Date: 17-10-2014
DOI: 10.1183/09031936.00105013
Abstract: Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1β is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1β requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1β endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1β determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1β in participants with neutrophilic asthma. Protein levels of IL-1β were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1β.
Absence of Toll–IL-1 Receptor 8/Single Immunoglobulin IL-1 Receptor–Related Molecule Reduces House Dust Mite–Induced Allergic Airway Inflammation in Mice
Publisher: American Thoracic Society
Date: 09-2013
Eosinophils in repair and remodelling
Publisher: Wiley
Date: 12-2004
Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity
Publisher: Elsevier BV
Date: 06-2010
Bone marrow regulatory T cells are a unique population, supported by niche-specific cytokines and plasmacytoid dendritic cells, and required for chronic graft-vs-host disease control
Publisher: Frontiers Media SA
Date: 22-09-2021
DOI: 10.3389/FCELL.2021.737880
Abstract: Regulatory T cell (Treg) reconstitution is essential for reestablishing tolerance and maintaining homeostasis following stem-cell transplantation. We previously reported that bone marrow (BM) is highly enriched in autophagy-dependent Treg and autophagy disruption leads to a significant Treg loss, particularly BM-Treg. To correct the known Treg deficiency observed in chronic graft-versus-host disease (cGVHD) patients, low dose IL-2 infusion has been administered, substantially increasing peripheral Treg (pTreg) numbers. However, as clinical responses were only seen in ∼50% of patients, we postulated that pTreg augmentation was more robust than for BM-Treg. We show that BM-Treg and pTreg have distinct characteristics, indicated by differential transcriptome expression for chemokine receptors, transcription factors, cell cycle control of replication and genes linked to Treg function. Further, BM-Treg were more quiescent, expressed lower FoxP3, were highly enriched for co-inhibitory markers and more profoundly depleted than splenic Treg in cGVHD mice. In vivo our data are consistent with the BM and not splenic microenvironment is, at least in part, driving this BM-Treg signature, as adoptively transferred splenic Treg that entered the BM niche acquired a BM-Treg phenotype. Analyses identified upregulated expression of IL-9R, IL-33R, and IL-7R in BM-Treg. Administration of the T cell produced cytokine IL-2 was required by splenic Treg expansion but had no impact on BM-Treg, whereas the converse was true for IL-9 administration. Plasmacytoid dendritic cells (pDCs) within the BM also may contribute to BM-Treg maintenance. Using pDC-specific BDCA2-DTR mice in which diptheria toxin administration results in global pDC depletion, we demonstrate that pDC depletion h ers BM, but not splenic, Treg homeostasis. Together, these data provide evidence that BM-Treg and splenic Treg are phenotypically and functionally distinct and influenced by niche-specific mediators that selectively support their respective Treg populations. The unique properties of BM-Treg should be considered for new therapies to reconstitute Treg and reestablish tolerance following SCT.
Toll/IL-1 Signaling Is Critical for House Dust Mite–specific Th1 and Th2 Responses
Publisher: American Thoracic Society
Date: 15-05-2009
Viral and host factors determine innate immune responses in airway epithelial cells from children with wheeze and atopy
Publisher: BMJ
Date: 07-05-2014
Acute Allergen-Induced Airway Remodeling in Atopic Asthma
Publisher: American Thoracic Society
Date: 12-2004
Regulation of inducible BALT formation and contribution to immunity and pathology
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1038/MI.2010.52
Abstract: Inducible bronchus-associated lymphoid tissue (iBALT) is an organized tertiary lymphoid structure that is not pre-programmed but develops in response to infection or under chronic inflammatory conditions. Emerging research has shown that iBALT provides a niche for T-cell priming and B-cell education to assist in the clearance of infectious agents, highlighting the prospect that iBALT may be engineered and harnessed to enhance protective immunity against respiratory pathogens. Although iBALT formation is associated with several canonical factors of secondary lymphoid organogenesis such as lymphotoxin-α and the homeostatic chemokines, CXCL13, CCL19, and CCL21, these cytokines are not mandatory for its formation, even though they influence its organization and function. Similarly, lymphoid tissue-inducer cells are not a requisite of iBALT formation. In contrast, dendritic cells are emerging as pivotal players required to form and sustain the presence of iBALT. Regulatory T cells appear to be able to attenuate the development of iBALT, although the underlying mechanisms remain ill-defined. In this review, we discuss facets unique to iBALT induction, the cellular subsets, and molecular cues that govern this process, and the contribution of this ectopic structure toward the generation of immune responses in the pulmonary compartment.
Soluble heparan sulfate fragments generated by heparanase trigger the release of pro-inflammatory cytokines through TLR-4.
Publisher: Public Library of Science (PLoS)
Date: 08-10-2014
Mice deficient in heparanase exhibit impaired dendritic cell migration and reduced airway inflammation.
Publisher: Wiley
Date: 14-02-2014
Abstract: Heparanase is a β-d-endoglucuronidase that cleaves heparan sulphate, a key component of the ECM and basement membrane. The remodelling of the ECM by heparanase has been proposed to regulate both normal physiological and pathological processes, including wound healing, inflammation, tumour angiogenesis and cell migration. Heparanase is also known to exhibit non-enzymatic functions by regulating cell adhesion, cell signalling and differentiation. In this study, constitutive heparanase-deficient (Hpse(-/-) ) mice were generated on a C57BL/6 background using the Cre/loxP recombination system, with a complete lack of heparanase mRNA, protein and activity. Although heparanase has been implicated in embryogenesis and development, Hpse(-/-) mice are anatomically normal and fertile. Interestingly, consistent with the suggested function of heparanase in cell migration, the trafficking of dendritic cells from the skin to the draining lymph nodes was markedly reduced in Hpse(-/-) mice. Furthermore, the ability of Hpse(-/-) mice to generate an allergic inflammatory response in the airways, a process that requires dendritic cell migration, was also impaired. These findings establish an important role for heparanase in immunity and identify the enzyme as a potential target for regulation of an immune response.
Th2/Th17 reciprocal regulation: twists and turns in the complexity of asthma phenotypes
Publisher: AME Publishing Company
Date: 10-2016
Eosinophils: Biological Properties and Role in Health and Disease
Publisher: Wiley
Date: 04-2008
DOI: 10.1111/J.1365-2222.2008.02958.X
Abstract: Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of erse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
The contribution of toll‐like receptors to the pathogenesis of asthma
Publisher: Wiley
Date: 08-2007
Abstract: Asthma is a major disease in the westernized world and its incidence has significantly increased over the past 40 years. Our understanding of the pathogenesis of asthma remains rudimentary, and for this reason, little has been accomplished by way of targeted intervention, either at a population level (to reduce the overall prevalence) or at an in idual level (to treat the cause). Instead, the management strategy currently in use relies on broad-spectrum anti-inflammatory agents, generally glucocorticoids and long-acting beta2 agonists. The recent discovery of toll-like receptors (TLRs), with their role as the initiators of the innate immune response and inflammation, suggests that modulating these receptors may be beneficial in the treatment of allergic disorders. We review here the cellular distribution of TLR in the lung and their potential contribution to the processes that promote T helper 2 (Th2) immunity and infection-induced exacerbations of allergic lung disease.
Early production of thymic stromal lymphopoietin precedes infiltration of dendritic cells expressing its receptor in allergen‐induced late phase cutaneous responses in atopic subjects
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1398-9995.2009.01947.X
Abstract: Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses through a receptor consisting of a heterodimer of the IL-7 receptor alpha (IL-7Ralpha) chain and the TSLP receptor (TSLPR), which resembles the cytokine receptor common gamma chain. Dendritic cells activated by TSLP prime development of CD4(+) T cells into Th2 cells contributing to the pathogenesis of allergic inflammation. We hypothesized that allergen exposure induces expression of TSLP and results in recruitment of TSLPR bearing cells in the cutaneous allergen-induced late-phase reaction (LPR) in atopic subjects. Skin biopsies were obtained from atopic subjects (n = 9) at various times after cutaneous allergen challenge. In situ hybridization and immunohistochemistry were used to determine TSLP mRNA expression and to measure infiltration of TSLPR(+) DC in skin LPR. RT-PCR and flow cytometry were employed to analyse TSLPR expression on isolated blood DC. Allergen-induced skin TSLP expression occurred as early as 1 h after allergen challenge, whereas TSLPR(+) and CD11c(+) cells infiltrated relatively late (24-48 h). The majority of TSLPR(+) cells were DC co-expressing blood DC antigen-1 (BDCA-1) or BDCA-2. Freshly isolated blood DC expressed both TSLPR and IL-7Ralpha chains. Maturation and stimulation with TSLP or polyriboinosinic-polyribocytidylic acid in vitro upregulated the expression of both TSLPR and IL-7Ralpha chains in DC but not in chemoattractant receptor-homologous molecule expressed on Th2 cells(+) CD4(+) T cells. The data suggest that TSLP plays a role in augmenting, through DC recruitment and activation, the development of Th2-type T cells in allergic inflammation.
Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia
Publisher: BMJ
Date: 24-06-2015
Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection
Publisher: Elsevier BV
Date: 05-2023
Critical Role of Plasmacytoid Dendritic Cells in Regulating Gene Expression and Innate Immune Responses to Human Rhinovirus-16
Publisher: Frontiers Media SA
Date: 25-10-2017
The plasmacytoid dendritic cell: at the cross-roads in asthma
Publisher: European Respiratory Society (ERS)
Date: 21-02-2013
DOI: 10.1183/09031936.00203412
Abstract: The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host's antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function. Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance. Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma.
Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JACI.2016.02.039
Abstract: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production. We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion
Publisher: Rockefeller University Press
Date: 22-12-2017
DOI: 10.1084/JEM.20170298
Abstract: Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
Modulation of Vagal Sensory Neurons via High Mobility Group Box-1 and Receptor for Advanced Glycation End Products: Implications for Respiratory Viral Infections.
Publisher: Frontiers Media SA
Date: 21-09-2021
DOI: 10.3389/FPHYS.2021.744812
Abstract: Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes to their morphological and functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator of pulmonary inflammation and can have actions on neurons in a range of inflammatory settings. We hypothesized that HMGB1 can regulate the growth and function of vagal sensory neurons and we set out to investigate this and the mechanisms involved. Culturing primary vagal sensory neurons from wildtype mice in the presence of HMGB1 significantly increased neurite outgrowth, while acute application of HMGB1 to isolated neurons under patch cl electrophysiological investigation produced inward currents and enhanced action potential firing. Transcriptional analyses revealed the expression of the cognate HMGB1 receptors, Receptor for Advanced Glycation End products (RAGE) and Toll-like Receptor 4 (TLR4), in subsets of vagal sensory neurons. HMGB1-evoked growth and electrophysiological responses were significantly reduced in primary vagal sensory neurons harvested from RAGE deficient mice and completely absent in neurons from RAGE/TLR4 double deficient mice. Immunohistochemical analysis of vagal sensory neurons collected from mice after intranasal infection with murine pneumovirus or influenza A virus (IAV), or after intratracheal administration with the viral mimetic PolyI:C, revealed a significant increase in nuclear-to-cytoplasm translocation of HMGB1 compared to mock-inoculated mice. Neurons cultured from virus infected wildtype mice displayed a significant increase in neurite outgrowth, which was not observed for neurons from virus infected RAGE or RAGE/TLR4 deficient mice. These data suggest that HMGB1 can enhance vagal sensory neuron growth and excitability, acting primarily via sensory neuron RAGE. Activation of the HMGB1-RAGE axis in vagal sensory neurons could be an important mechanism leading to vagal hyperinnervation and hypersensitivity in chronic pulmonary disease.
Long-lived regulatory T cells generated during severe bronchiolitis in infancy influence later progression to asthma.
Publisher: Elsevier BV
Date: 07-2020
The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis
Publisher: Cold Spring Harbor Laboratory
Date: 06-01-2023
DOI: 10.1101/2023.01.05.522516
Abstract: Severe lower respiratory infection (sLRI) are a major cause of infant morbidity and mortality, and predispose to later chronic respiratory diseases such as asthma. Poor maternal diet during pregnancy is a risk factor for sLRI in the offspring. Here we demonstrate in mice that a maternal low-fibre diet (LFD) disrupts plasmacytoid and conventional dendritic cell (DC) hematopoiesis in the offspring, predisposing to sLRI and subsequent asthma. The LFD alters the composition of the maternal milk microbiome and assembling infant gut microbiome, ablating the induction of a developmental wave of the non-redundant DC growth factor Flt3L by neonatal intestinal epithelial cells. Therapy with a propionate-producing bacteria isolated from the milk of high-fibre diet-fed mothers, or supplementation with propionate, confers protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that regulates pDC hematopoiesis in early life and confers disease resistance.
Related Organisations
University Of Bath
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
ARC Future Fellowships - Grant ID: FT130100518
Start Date: 2014
End Date: 2018
Amount: $754,320.00
Funder: Australian Research Council
View Funded Activity