ORCID Profile
0000-0002-6540-1281
Current Organisation
Hudson Institute of Medical Research
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Publications
The Inflammasome Contributes to Depletion of the Ovarian Reserve During Aging in Mice
Publisher: Frontiers Media SA
Date: 11-02-2021
DOI: 10.3389/FCELL.2020.628473
Abstract: Ovarian aging is a natural process characterized by follicular depletion and a reduction in oocyte quality, resulting in loss of ovarian function, cycle irregularity and eventually infertility and menopause. The factors that contribute to ovarian aging have not been fully characterized. Activation of the NLRP3 inflammasome has been implicated in age-associated inflammation and diminished function in several organs. In this study, we used Asc −/− and Nlrp3 −/− mice to investigate the possibility that chronic low-grade systemic inflammation mediated by the inflammasome contributes to diminished ovarian reserves as females age. Pro-inflammatory cytokines, IL-6, IL-18, and TNF-α, were decreased in the serum of aging Asc −/− mice compared to WT. Within the ovary of reproductively aged Asc −/− mice, mRNA levels of major pro-inflammatory genes Tnfa, Il1a, and Il1b were decreased, and macrophage infiltration was reduced compared to age-matched WT controls. Notably, suppression of the inflammatory phenotype in Asc −/− mice was associated with retention of follicular reserves during reproductive aging. Similarly, the expression of intra-ovarian pro-inflammatory cytokines was reduced, and follicle numbers were significantly elevated, in aging Nlrp3 −/− mice compared to WT controls. These data suggest that inflammasome-dependent inflammation contributes to the age-associated depletion of follicles and raises the possibility that ovarian aging could be delayed, and fertile window prolonged, by suppressing inflammatory processes in the ovary.
Lipopolysaccharide-Deficient Acinetobacter baumannii Shows Altered Signaling through Host Toll-Like Receptors and Increased Susceptibility to the Host Antimicrobial Peptide LL-37
Publisher: American Society for Microbiology
Date: 03-2013
DOI: 10.1128/IAI.01362-12
Abstract: Infections caused by multidrug-resistant Acinetobacter baumannii have emerged as a serious global health problem. We have shown previously that A. baumannii can become resistant to the last-line antibiotic colistin via the loss of lipopolysaccharide (LPS), including the lipid A anchor, from the outer membrane (J. H. Moffatt, M. Harper, P. Harrison, J. D. Hale, E. Vinogradov, T. Seemann, R. Henry, B. Crane, F. St. Michael, A. D. Cox, B. Adler, R. L. Nation, J. Li, and J. D. Boyce, Antimicrob. Agents Chemother. 54: 4971–4977, 2010). Here, we show how these LPS-deficient bacteria interact with components of the host innate immune system. LPS-deficient A. baumannii stimulated 2- to 4-fold lower levels of NF-κB activation and tumor necrosis factor alpha (TNF-α) secretion from immortalized murine macrophages, but it still elicited low levels of TNF-α secretion via a Toll-like receptor 2-dependent mechanism. Furthermore, we show that while LPS-deficient A. baumannii was not altered in its resistance to human serum, it showed increased susceptibility to the human antimicrobial peptide LL-37. Thus, LPS-deficient, colistin-resistant A. baumannii shows significantly altered activation of the host innate immune inflammatory response.
MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses
Publisher: Elsevier BV
Date: 09-2009
If a butterfly flaps its wings in the Amazon, do we form an Inflammasome?
Publisher: Elsevier BV
Date: 06-2017
IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3
Publisher: The American Association of Immunologists
Date: 15-01-2011
Abstract: Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated by TLR4 and involve the coordinated production of a multitude of inflammatory mediators, especially IL-6, which signals via the shared IL-6 cytokine family receptor subunit gp130. However, the exact role of IL-6, which can elicit either proinflammatory or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signaling pathways activated by IL-6 in a proinflammatory state, remain unclear. To define the contribution of gp130 signaling events to TLR4-driven inflammatory responses, we combined genetic and therapeutic approaches based on a series of gp130F/F knock-in mutant mice displaying hyperactivated IL-6–dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130F/F mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-α. In gp130F/F mice, either genetic ablation of IL-6, Ab-mediated inhibition of IL-6R signaling or therapeutic blockade of IL-6 trans-signaling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT3 activity in gp130F/F:Stat3+/− mice alleviated LPS hypersensitivity and reduced LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130F/F mice. Collectively, these data demonstrate for the first time, to our knowledge, that IL-6 trans-signaling via STAT3 is a critical modulator of LPS-driven proinflammatory responses through cross-talk regulation of the TLR4/Mal signaling pathway, and potentially implicate cross-talk between JAK/STAT and TLR pathways as a broader mechanism that regulates the severity of the host inflammatory response.
Evaluation of inflammation and follicle depletion during ovarian ageing in mice
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1038/S41598-020-79488-4
Abstract: Reproductive ageing in females is defined by a progressive decline in follicle number and oocyte quality. This is a natural process that leads to the loss of fertility and ovarian function, cycle irregularity and eventually menopause or reproductive senescence. The factors that underlie the natural depletion of follicles throughout reproductive life are poorly characterised. It has been proposed that inflammatory processes and fibrosis might contribute to ovarian ageing. To further investigate this possibility, we evaluated key markers of inflammation and immune cell populations in the ovaries of 2, 6, 12 and 18-month-old C57BL/6 female mice. We report that the decrease in follicle numbers over the reproductive lifespan was associated with an increase in the intra-ovarian percentage of CD4 + T cells, B cells and macrophages. Serum concentration and intra-ovarian mRNA levels of several pro-inflammatory cytokines, including IL-1α/β, TNF-α, IL-6, and inflammasome genes ASC and NLRP3, were significantly increased with age. Fibrosis levels, as determined by picrosirius red staining for collagen I and III, were unchanged up to 18 months of age. Collectively, these data suggest that inflammation could be one of the mechanisms responsible for the age-related regulation of follicle number, but the role of fibrosis is unclear. Further studies are now required to determine if there is a causative relationship between inflammation and follicle depletion as females age.
A type III effector antagonizes death receptor signalling during bacterial gut infection
Publisher: Springer Science and Business Media LLC
Date: 08-2021
DOI: 10.1038/NATURE12524
Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.PHRS.2016.12.015
Abstract: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2 n=7-8 P 0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain.
Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling
Publisher: Springer Science and Business Media LLC
Date: 31-07-2017
DOI: 10.1038/NSMB.3444
TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target
Publisher: Oxford University Press (OUP)
Date: 09-05-2016
Abstract: Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR signaling for therapeutic benefit.
The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF
Publisher: Springer Science and Business Media LLC
Date: 13-04-2015
DOI: 10.1038/NCOMMS7795
Abstract: To date, the activities of protein kinases have formed the core of our understanding of cell signal transduction. Comprehension of the extent of protein acetylation has raised expectations that this alternate post-transcriptional modification will be shown to rival phosphorylation in its importance in mediating cellular responses. However, limited instances have been identified. Here we show that signalling from Toll-like or TNF-α receptors triggers the calcium/calmodulin-dependent protein kinase (CaMK2) to activate histone acetyltransferase-1 (HAT1), which then acetylates the transcriptional regulator PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF-κB p50 subunit that limits the NF-κB response. Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. These results identify a central role for acetylation in controlling the inflammatory NF-κB transcriptional programme.
BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs
Publisher: Proceedings of the National Academy of Sciences
Date: 20-01-2015
Abstract: Maintaining physiological balance is vital in the primary response to infectious and other stress stimuli to avert damaging inflammation. Delineation of the cell regulatory processes that control inflammatory processes better enable the development of informed strategies to treat associated pathologies. Toward this end, we identify that the promyelocytic leukemia zinc finger (PLZF) transcription factor limits pathogen-induced inflammation. PLZF stabilizes a repressor complex that encompasses histone deacetylase activity, which modifies the state of chromatin. This activity maintains homeostasis by decreasing the scale of induction of select immune response genes. In the absence of PLZF, the chromatin structure is altered, enabling active transcriptional complexes to immediately assemble on gene promoters, resulting in inordinate production of inflammatory cytokines.
Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses
Publisher: Proceedings of the National Academy of Sciences
Date: 30-01-2014
Abstract: IL-37 exerts broad inhibitory properties on the innate inflammatory and acquired immune responses. We mutated the caspase-1 site in IL-37 and show that caspase-1 processing is required for maturation of the intracellular IL-37 precursor for its translocation to the nucleus. Because nuclear translocation of IL-37 is required for the suppression of LPS-induced IL-6, the data define a unique consequence for caspase-1 inhibition, that is, reversal of the anti-inflammatory activities of endogenous IL-37. In addition, neutralizing antibodies reverse the suppression of LPS-induced IL-6 in IL-37 transgenic mice, supporting a role for extracellular signaling by IL-37. Thus, similar to IL-1α and IL-33, IL-37 now emerges as a dual-function cytokine with both intra- and extracellular mechanisms of action.
Adaptors in toll-like receptor signaling and their potential as therapeutic targets
Publisher: Bentham Science Publishers Ltd.
Date: 08-2012
DOI: 10.2174/138945012803530260
Abstract: To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group. Other TIR domain-containing proteins have also been shown to regulate these signaling pathways, including ST2 and SIGIRR, as well as several bacterial and viral TIR domain-containing proteins that modulate these pathways as virulence factors. TLR pathways and the adaptor proteins are associated with a number of diseases, including infection, sepsis, inflammatory, allergic and autoimmune diseases and cancer. We review our current understanding of the structure and function of adaptor proteins and their regulatory proteins, their association with disease and their potential as therapeutic targets in human disease.
HIV Blocks Interferon Induction in Human Dendritic Cells and Macrophages by Dysregulation of TBK1
Publisher: American Society for Microbiology
Date: 07-2015
DOI: 10.1128/JVI.00889-15
Abstract: Dendritic cells (DCs) and macrophages are present in the tissues of the anogenital tract, where HIV-1 transmission occurs in almost all cases. These cells are both target cells for HIV-1 and represent the first opportunity for the virus to interfere with innate recognition. Previously we have shown that both cell types fail to produce type I interferons (IFNs) in response to HIV-1 but that, unlike T cells, the virus does not block IFN induction by targeting IFN regulatory factor 3 (IRF3) for cellular degradation. Thus, either HIV-1 inhibits IFN induction by an alternate mechanism or, less likely, these cells fail to sense HIV-1. Here we show that HIV-1 (but not herpes simplex virus 2 [HSV-2] or Sendai virus)-exposed DCs and macrophages fail to induce the expression of all known type I and III IFN genes. These cells do sense the virus, and pattern recognition receptor (PRR)-induced signaling pathways are triggered. The precise stage in the IFN-inducing signaling pathway that HIV-1 targets to block IFN induction was identified phosphorylation but not K63 polyubiquitination of TANK-binding kinase 1 (TBK1) was completely inhibited. Two HIV-1 accessory proteins, Vpr and Vif, were shown to bind to TBK1, and their in idual deletion partly restored IFN-β expression. Thus, the inhibition of TBK1 autophosphorylation by binding of these proteins appears to be the principal mechanism by which HIV-1 blocks type I and III IFN induction in myeloid cells. IMPORTANCE Dendritic cells (DCs) and macrophages are key HIV target cells. Therefore, definition of how HIV impairs innate immune responses to initially establish infection is essential to design preventative interventions, especially by restoring initial interferon production. Here we demonstrate how HIV-1 blocks interferon induction by inhibiting the function of a key kinase in the interferon signaling pathway, TBK1, via two different viral accessory proteins. Other viral proteins have been shown to target the general effects of TBK1, but this precise targeting between ubiquitination and phosphorylation of TBK1 is novel.
A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases
Publisher: Wiley
Date: 2023
DOI: 10.1002/CTI2.1455
Abstract: Inflammasomes induce maturation of the inflammatory cytokines IL‐1β and IL‐18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small‐molecule inhibitors to target inflammasome activity and reduce disease‐associated inflammatory burden. We examined the therapeutic potential of a novel small‐molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome‐mediated inflammation in vivo . In vitro , we characterised ADS032 function, target engagement and specificity. We describe ADS032 as the first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL‐1β in human‐derived macrophages and bronchial epithelial cells in response to the activation of NLPR1 and NLRP3. ADS032 also reduced NLRP3‐induced ASC speck formation, indicative of targeting inflammasome formation. In vivo , ADS032 reduced IL‐1β and TNF‐α levels in the serum of mice challenged i.p. with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Critically, ADS032 protected mice from lethal influenza A virus challenge, displayed increased survival and reduced pulmonary inflammation. ADS032 is the first described dual inflammasome inhibitor and a potential therapeutic to treat both NLRP1‐ and NLRP3‐associated inflammatory diseases and also constitutes a novel tool that allows examination of the role of NLRP1 in human disease.
IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
DOI: 10.1161/HYPERTENSIONAHA.120.16437
Abstract: IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18 −/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K lacebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3 + T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18 −/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18 −/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K lacebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.
Mitochondrially localised MUL1 is a novel modulator of antiviral signaling.
Publisher: Wiley
Date: 12-02-2013
DOI: 10.1038/ICB.2013.7
Abstract: The innate immune response to virus must be balanced to eliminate infection yet limit damaging inflammation. A critical arm of the antiviral response is launched by the retinoic acid-inducible-gene I (RIG-I) protein. RIG-I is activated by viral RNA then associates with the mitochondrial antiviral signaling (MAVS) protein to subsequently induce potent inflammatory cytokines. Here, we demonstrate the mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is a crucial moderator of RIG-I signaling. MUL1 is localized to the mitochondria where it interacts with MAVS and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiated RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosted the antiviral response and increased proinflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. We therefore submit that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.
The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4
Publisher: Oxford University Press (OUP)
Date: 08-05-2014
Abstract: TLRs act as sentinels in professional immune cells to detect and initiate the innate immune response to pathogen challenge. TLR4 is a widely expressed TLR, responsible for initiating potent immune responses to LPS. TRAM acts to bridge TLR4 with TRIF, orchestrating the inflammatory response to pathogen challenge. We have identified a putative TRAF6-binding motif in TRAM that could mediate a novel signaling function for TRAM in TLR4 signaling. TRAM and TRAF6 association was confirmed by immunoprecipitation of endogenous, ectopically expressed and recombinant proteins, which was ablated upon mutation of a key Glu residue in TRAM (TRAM E183A). TRAF6 and TRAM were observed colocalizing using confocal microscopy following ectopic expression in cells and the ability of TRAM and TRAM E183A to activate luciferase-linked reporter assays was determined in HEK293 and TRAF6-deficient cells. Importantly, TRAM-deficient macrophages reconstituted with TRAM E183A display significantly reduced inflammatory TNF-α, IL-6, and RANTES protein production compared with WT TRAM. These results demonstrate a novel role for TRAM in TLR4-mediated signaling in regulating inflammatory responses via its interaction with TRAF6, distinct from its role as a bridging adaptor between TLR4 and TRIF.
Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase‐1 and p38 MAP kinase
Publisher: Wiley
Date: 19-01-2006
DOI: 10.1016/J.FEBSLET.2006.01.027
Abstract: The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is induced by glucocorticoids (GCs), but it was not previously known if MIF regulates cellular sensitivity to GC. Here we show in GC and LPS-treated peritoneal macrophages derived from MIF-/- and wt mice that the absence of endogenous MIF is associated with increased sensitivity to GC of TNF release. This is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), concomitant decreased phosphorylation of p38 MAPK, but no effect of MIF on nuclear factor kappaB (NF-kappaB). These results demonstrate that MIF regulates GC sensitivity by phosphorylation of p38, and provides a cellular mechanism for this observation, indicating that MKP-1 is a central target of this regulation.
The negative regulation of Toll‐like receptor and associated pathways
Publisher: Wiley
Date: 10-07-2007
Abstract: Toll-like receptors (TLRs) are essential mediators of both innate and adaptive immunity by recognizing and eliciting responses upon invasion of pathogens. The response of TLRs must be stringently regulated as exaggerated expression of signalling components as well as pro-inflammatory cytokines can have devastating effects on the host, resulting in chronic inflammatory diseases, autoimmune disorders and aid in the pathogenesis of TLR-associated human diseases. Therefore, it is essential that negative regulators act at multiple levels within TLR signalling cascades, as well as through eliciting negative-feedback mechanisms in order to synchronize the positive activation and negative regulation of signal transduction to avert potentially harmful immunological consequences. This review explores the various mechanisms employed by negative regulators to ensure the appropriate modulation of both immune and inflammatory responses.
Life is so much easier for the sea urchin
Publisher: Wiley
Date: 08-2007
Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.AJPATH.2014.01.023
Abstract: In acute kidney injury, which is a significant cause of morbidity and mortality, cytokines and leukocytes promote inflammation and injury. We examined the pathogenic role of IL-17A in cisplatin-induced acute kidney injury. Intrarenal IL-17A mRNA transcription and protein expression were increased in wild-type mice after cisplatin-induced renal injury. An important role for IL-17A in the nephrotoxicity of cisplatin was demonstrated by observing protection from cisplatin-induced functional and histological renal injury in Il17a(-/-) and Rorγt(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1β and IL-17A production were attenuated in Asc(-/-) and Tlr2(-/-) mice, suggesting that cisplatin induces endogenous TLR2 ligand production and activates the ASC-dependent inflammasome complex, resulting in IL-1β and injurious IL-17A production. Neutrophils and natural killer cells are the likely targets of these pathways, because combined depletion of these cells was strongly protective anti-IL-17A antibodies had no additional effect in this setting. Although IL-17A can also be produced by CD4(+) and γδ T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in γδ T-cell-deficient mice, whereas Il17a(-/-) CD4(+) T cells induced similar injury as did wild-type CD4(+) T cells on transfer to cisplatin-injected Rag1(-/-) mice. These studies demonstrate an important role for TLR2, the ASC inflammasome, and IL-17A in innate leukocytes in cisplatin-induced renal injury.
An update on the NLRP3 inflammasome and influenza: the road to redemption or perdition?
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.COI.2018.06.005
Abstract: Inflammation is an integral aspect of influenza A virus (IAV) infection. It is critical to induce an antiviral environment to reduce viral replication and dissemination, while also being essential to the development and maturation of adaptive immunity, which ultimately resolves infection. Conversely, excessive pulmonary inflammation and cellular influx are characteristic of lethal IAV infections. It has become increasingly apparent that the innate immune inflammasome complex is a crucial moderator in IAV disease pathogenesis. It is responsible for the maturation and secretion of prototypic inflammatory cytokines, Interleukin (IL)-1β and IL-18, and the induction of pyroptotic cell death. This short review will examine recent work on the regulation and targeting of the NLRP3 inflammasome as a means of intrinsic and extrinsic modulation of inflammasome-mediated inflammation. It is encouraging that recent studies suggest 'starving' the inflammasome of substrate, or directly inhibiting activity, may be the means to reducing host inflammatory responses to IAV infection and to directing a positive disease outcome.
The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages
Publisher: Wiley
Date: 28-09-2017
Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress
Publisher: Impact Journals, LLC
Date: 28-06-2017
A novel function of InlB from Listeria monocytogenes: activation of NF-kappaB in J774 macrophages
Publisher: Hindawi Limited
Date: 04-2000
DOI: 10.1046/J.1462-5822.2000.00038.X
Abstract: Listeria monocytogenes causes a pro-inflammatory response on adhesion to macrophages. Upregulation of inflammation genes involves the transcription factor NF-kappaB. Several components of L. monocytogenes, including lipoteichoic acid (LTA), phospholipases and listeriolysin O (LLO), have since been shown to mediate NF-kappaB activation. Here, we report that purified recombinant InlB, but not internalin (InlA), is a potent activator of NF-kappaB in the mouse macrophage-like cell line J774. Expression of InlB in Listeria innocua enhances its ability to activate NF-kappaB, while deletion of InlB from L. monocytogenes marginally decreases its effect on NF-kappaB, possibly because of the presence of NF-kappaB activators such as LTA and LLO. The effect correlates with the rapid degradation of IkappaBalpha, a sustained degradation of IkappaBbeta and increases in tumour necrosis factor alpha (TNF-alpha) and interleukin (IL) 6 production, two cytokines controlled by NF-kappaB. Using a series of anti-InlB monoclonal antibodies and domains of InlB, NF-kappaB activation was shown to be dependent upon the N-terminal 213-amino-acid leucine-rich repeat (LRR) domain of InlB, recently demonstrated to be responsible for InlB-mediated L. monocytogenes invasion and phosphoinositide-3 (PI-3) kinase activation. The effect of InlB was blocked by PI-3 kinase inhibitors, indicating the involvement of PI-3 kinase in this response. This report thus illustrates that InlB not only promotes invasion, but also contributes to the macrophage pro-inflammatory response.
Crystallization and X-ray diffraction analysis of the N-terminal domain of the Toll-like receptor signalling adaptor protein TRIF/TICAM-1
Publisher: International Union of Crystallography (IUCr)
Date: 28-06-2013
NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice
Publisher: Springer Science and Business Media LLC
Date: 26-06-2023
DOI: 10.1038/S41467-023-39487-1
Abstract: The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori . Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori -induced pathology.
Disruption of Serinc1, which facilitates serine-derived lipid synthesis, fails to alter macrophage function, lymphocyte proliferation or autoimmune disease susceptibility
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.MOLIMM.2016.12.007
Abstract: During immune cell activation, serine-derived lipids such as phosphatidylserine and sphingolipids contribute to the formation of protein signaling complexes within the plasma membrane. Altering lipid composition in the cell membrane can subsequently affect immune cell function and the development of autoimmune disease. Serine incorporator 1 (SERINC1) is a putative carrier protein that facilitates synthesis of serine-derived lipids. To determine if SERINC1 has a role in immune cell function and the development of autoimmunity, we characterized a mouse strain in which a retroviral insertion abolishes expression of the Serinc1 transcript. Expression analyses indicated that the Serinc1 transcript is readily detectable and expressed at relatively high levels in wildtype macrophages and lymphocytes. The ablation of Serinc1 expression in these immune cells, however, did not significantly alter serine-derived lipid composition or affect macrophage function and lymphocyte proliferation. Analyses of Serinc1-deficient mice also indicated that systemic ablation of Serinc1 expression did not affect viability, fertility or autoimmune disease susceptibility. These results suggest that Serinc1 is dispensable for certain immune cell functions and does not contribute to previously reported links between lipid composition in immune cells and autoimmunity.
STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression
Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1038/S41467-020-17669-5
Abstract: Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.
Mal Interacts with Tumor Necrosis Factor Receptor-associated Factor (TRAF)-6 to mediate NF-κB Activation by Toll-like Receptor (TLR)-2 and TLR4
Publisher: Elsevier BV
Date: 09-2004
Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice
Publisher: Bioscientifica
Date: 08-2020
DOI: 10.1530/JOE-20-0161
Abstract: MR activation in macrophages is critical for the development of cardiac inflammation and fibrosis. We previously showed that MR activation modifies macrophage pro-inflammatory signalling, changing the cardiac tissue response to injury via both direct gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated renal electrolyte homeostasis is critically determined by DNA-binding-dependent processes. Hence, ascertaining the relative contribution of MR actions via DNA binding or alternative pathways on macrophage behaviour and cardiac inflammation may provide therapeutic opportunities which separate the cardioprotective effects of MR antagonists from their undesirable renal potassium-conserving effects. We developed new macrophage cell lines either lacking MR or harbouring a mutant MR incapable of DNA binding. Western blot analysis demonstrated that MR DNA binding is required for lipopolysaccharide (LPS), but not phorbol 12-myristate-13-acetate (PMA), induction of the MAPK JNK pathway in macrophages. Quantitative RTPCR for pro-inflammatory and pro-fibrotic targets revealed subsets of LPS- and PMA-induced genes that were either enhanced or repressed by the MR via actions that do not always require direct MR-DNA binding. Analysis of the MR target gene and profibrotic factor MMP12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. Evaluation of cardiac tissue responses to an 8-day DOC/salt challenge in mice selectively lacking MR DNA-binding in macrophages demonstrated levels of inflammatory markers equivalent to WT, indicating non-DNA binding-dependent MR signalling in macrophages is sufficient for DOC/salt-induced tissue inflammation. Our data demonstrate that the MR regulates a macrophage pro-inflammatory phenotype and cardiac tissue inflammation, partially via pathways that do not require DNA binding.
The Hepatitis B e antigen (HBeAg) targets and suppresses activation of the Toll-like receptor signaling pathway
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.JHEP.2010.12.042
Abstract: Viruses target innate immune pathways to evade host antiviral responses. Recent studies demonstrate a relationship between hepatitis B disease states and the host's innate immune response, although the mechanism of immunomodulation is unknown. In humans, the innate immune system recognizes pathogens via pattern recognition receptors such as the Toll-like receptors (TLR), initiating anti-inflammatory responses. TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (HBeAg)-positive patients following TLR stimulation. The aim of this study was to investigate interactions between TLR signaling pathways and the mature HBeAg protein localized in the cytosol. The ability of HBeAg to inhibit TLR signaling and association with TLR adapters was evaluated by immunoprecipitation, immunostaining, and reporter studies. Our findings show that HBeAg co-localizes with Toll/IL-1 receptor (TIR)-containing proteins TRAM, Mal, and TLR2 at the sub-cellular level, which was not observed for Hepatitis B core antigen. Co-immunoprecipitation analysis demonstrated HBeAg interacted with TIR proteins Mal and TRAM, while a mutated HBeAg ablated interaction between Mal and MyD88. Importantly, HBeAg also disrupted homotypic TIR:TIR interaction critical for TLR-mediated signaling. Finally, HBeAg suppressed TIR-mediated activation of the inflammatory transcription factors, NF-κB and Interferon-β promoter activity. Our study provides the first molecular mechanism describing HBeAg immunomodulation of innate immune signal transduction pathways via interaction and targeting of TLR-mediated signaling pathways. These finding suggest the mechanism as to how HBeAg evades innate immune responses contributing to the pathogenesis of chronic hepatitis B infection and the establishment of viral persistence.
Circulating BiP/Grp78 is a novel prognostic marker for sepsis‐mediated immune cell death
Publisher: Wiley
Date: 17-09-2020
DOI: 10.1111/FEBS.15552
Porphyromonas gingivalis Lipopolysaccharide Weakly Activates M1 and M2 Polarized Mouse Macrophages but Induces Inflammatory Cytokines
Publisher: American Society for Microbiology
Date: 10-2014
DOI: 10.1128/IAI.02325-14
Abstract: Porphyromonas gingivalis is associated with chronic periodontitis, an inflammatory disease of the tooth's supporting tissues. Macrophages are important in chronic inflammatory conditions, infiltrating tissue and becoming polarized to an M1 or M2 phenotype. As responses to stimuli differ between these phenotypes, we investigated the effect of P. gingivalis lipopolysaccharide (LPS) on M1 and M2 macrophages. M1 and M2 polarized macrophages were produced from murine bone marrow macrophages (BMMϕ) primed with gamma interferon (IFN-γ) or interleukin-4 (IL-4), respectively, and incubated with a low or high dose of P. gingivalis LPS or control TLR2 and TLR4 ligands. In M1-Mϕ, the high dose of P. gingivalis LPS (10 μg/ml) significantly increased the expression of CD40, CD86, inducible nitric oxide synthase, and nitric oxide secretion. The low dose of P. gingivalis LPS (10 ng/ml) did not induce costimulatory or antibacterial molecules but did increase the secretion of IL-1α, IL-6, IL-12p40, IL-12p70, and tumor necrosis factor alpha (TNF-α). P. gingivalis LPS marginally increased the expression of CD206 and YM-1, but it did enhance arginase expression by M2-Mϕ. Furthermore, the secretion of the chemokines KC, RANTES, eotaxin, and MCP-1 from M1, M2, and nonpolarized Mϕ was enhanced by P. gingivalis LPS. TLR2/4 knockout macrophages combined with the TLR activation assays indicated that TLR2 is the main activating receptor for P. gingivalis LPS and whole cells. In conclusion, although P. gingivalis LPS weakly activated M1-Mϕ or M2-Mϕ compared to control TLR ligands, it induced the secretion of inflammatory cytokines, particularly TNF-α from M1-Mϕ and IL-10 from M2-Mϕ, as well as chemotactic chemokines from polarized macrophages.
Toll-like receptor signalling and the clinical benefits that lie within
Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.1007/S00011-007-6093-7
Abstract: TLRs are of crucial importance to the innate immune system by recognising molecules that are broadly shared by pathogens but distinguishable from host molecules. The innate immune system works to defend the body from microbial infection by initiating inflammation, the extreme form of which is sepsis. The discovery that endogenous ligands, as well as microbial components, are recognised by TLRs, raise the possibility of these receptors and their associated adapter molecules, as potential targets for the development of agonists and antagonists for the treatment of various pathological diseases, and their manipulation as potential adjuvants in vaccine development. By elucidating the mechanisms of TLR signalling pathways involving adapter molecules like MyD88, Mal, TRIF and TRAM combined with the identification of single nucleotide polymorphisms (SNPs) within these receptors and the unique genes that are expressed upon recognition, will assist in the development of therapeutics to alleviate the consequences of microbial-mediated inflammation, which include inflammatory disorders and septic shock.
Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia
Publisher: Springer Science and Business Media LLC
Date: 2008
Signaling Molecules Affecting Immune Response
Publisher: Elsevier
Date: 2005
Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice
Publisher: Wiley
Date: 31-07-2016
DOI: 10.1111/BPH.13230
Toll-Like Receptors as Interferon-Regulated Genes and Their Role in Disease
Publisher: Mary Ann Liebert Inc
Date: 2011
Abstract: The Toll-like receptors (TLRs) are innate sensors that recognize both microbial and endogenous ligands, initiating the host defense response. TLRs initiate the potent proinflammatory response to infection, are the target for adjuvants, and are essential for the establishment and maturation of adaptive immunity. As such they have been the interest of widespread research and the target of therapeutic intervention on multiple diseases. It has become apparent that expression of a subset of TLRs (TLR1, TLR2, TLR3, TLR5, and TLR7) is induced by Type I interferons (IFN). The role and impact of IFN expression on TLR responses is therefore critical in understanding the role of TLRs in disease, particularly as IFN itself is a downstream gene induced by specific TLRs. In this review we discuss the function and role of IFN-regulated TLRs in disease and how the role of IFN may impact upon TLR induction of the immune response in diseases, particularly in mouse models.
Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition
Publisher: Springer Science and Business Media LLC
Date: 10-06-2016
DOI: 10.1038/SREP27912
Abstract: The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.
IRF7 in the Australian Black Flying Fox, Pteropus alecto: Evidence for a Unique Expression Pattern and Functional Conservation
Publisher: Public Library of Science (PLoS)
Date: 06-08-2014
Toll‐like receptors: the swiss army knife of immunity and vaccine development
Publisher: Wiley
Date: 05-2016
DOI: 10.1038/CTI.2016.22
Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation
Publisher: Springer Science and Business Media LLC
Date: 15-01-2006
DOI: 10.1038/NI1299
Abstract: Toll-like receptor (TLR) signals that initiate innate immune responses to pathogens must be tightly regulated to prevent excessive inflammatory damage to the host. The adaptor protein Mal is specifically involved in signaling via TLR2 and TLR4. We demonstrate here that after TLR2 and TLR4 stimulation Mal becomes phosphorylated by Bruton's tyrosine kinase (Btk) and then interacts with SOCS-1, which results in Mal polyubiquitination and subsequent degradation. Removal of SOCS-1 regulation potentiates Mal-dependent p65 phosphorylation and transactivation of NF-kappaB, leading to lified inflammatory responses. These data identify a target of SOCS-1 that regulates TLR signaling via a mechanism distinct from an autocrine cytokine response. The transient activation of Mal and subsequent SOCS-1-mediated degradation is a rapid and selective means of limiting primary innate immune response.
PB1-F2 peptide derived from avian influenza A virus H7N9 induces inflammation via activation of the NLRP3 inflammasome
Publisher: Elsevier BV
Date: 2017
Preclinical Mouse Model of Silicosis
Publisher: Springer US
Date: 2023
Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection
Publisher: Oxford University Press (OUP)
Date: 05-10-2017
Abstract: The severity of influenza A virus (IAV) infection can range from asymptotic to mild to severe. Infections, such as those seen following outbreaks of avian IAV, are associated with hyperinflammatory responses and the development of fatal disease. There is a continual threat that a novel or pandemic IAV will circulate in humans with high rates of mortality. The neuronal apoptosis inhibitor protein, class 2 transcription activator of the MHC, heterokaryon incompatibility, telomerase-associated protein 1, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an innate immune sensor that has been shown to be critical for the secretion of the potent proinflammatory cytokines, IL-1β and IL-18, as well as chemokine production and cellular inflammation in vivo following IAV infection. Initial studies illustrated a protective role of NLRP3 during severe IAV infection in mice. However, the NLRP3 inflammasome may be a hero that turns villain in the later stages of severe IAV infection via the promotion of a hyperinflammatory state. Current treatments for patients who present to hospitals with a severe IAV infection are limited. The understanding of the mechanisms involved in the induction of NLRP3-dependent inflammation during severe IAV infections may provide new therapeutic targets that reduce human mortality.
Alleviate the J–V hysteresis of carbon-based perovskite solar cells via introducing additional methylammonium chloride into MAPbI3 precursor
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8RA04347G
Abstract: The hysteretic phenomenon commonly exists in the J – V curves of perovskite solar cells with different structures, especially for carbon-based mesoscopic perovskite solar cells without hole-conductor (carbon-based PSCs).
On the functional diversity of dynamical behaviour in genetic and metabolic feedback systems
Publisher: Springer Science and Business Media LLC
Date: 11-05-2009
NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection
Publisher: Research Square Platform LLC
Date: 09-09-2020
DOI: 10.21203/RS.3.RS-49701/V1
Abstract: The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been well defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here, we report that the host defence molecule NOD1 regulates IL-18 processing in epithelial cells to the mucosal pathogens, Helicobacter pylori and Pseudomonas aeruginosa . We show that IL-18 is important in protecting against pre-neoplastic changes induced by gastric H. pylori infection in vivo . NOD1 mediates IL-18 processing via homotypic CARD-CARD interactions with caspase-1, and independently of canonical inflammasome proteins (NLRP3, ASC). These findings reveal an unanticipated role for NOD1 in the formation of bioactive IL-18, thereby underlining the differences in inflammasome functions between haematopoietic and non-haematopoietic cells.
Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection
Publisher: Proceedings of the National Academy of Sciences
Date: 22-08-2011
Abstract: Initiation of the innate immune response requires agonist recognition by pathogen-recognition receptors such as the Toll-like receptors (TLRs). Toll/interleukin-1 receptor (TIR) domain-containing adaptors are critical in orchestrating the signal transduction pathways after TLR and interleukin-1 receptor activation. Myeloid differentiation primary response gene 88 (MyD88) adaptor-like (MAL)/TIR domain-containing adaptor protein (TIRAP) is involved in bridging MyD88 to TLR2 and TLR4 in response to bacterial infection. Genetic studies have associated a number of unique single-nucleotide polymorphisms in MAL with protection against invasive microbial infection, but a molecular understanding has been h ered by a lack of structural information. The present study describes the crystal structure of MAL TIR domain. Significant structural differences exist in the overall fold of MAL compared with other TIR domain structures: A sequence motif comprising a β-strand in other TIR domains instead corresponds to a long loop, placing the functionally important “BB loop” proline motif in a unique surface position in MAL. The structure suggests possible dimerization and MyD88-interacting interfaces, and we confirm the key interface residues by coimmunoprecipitation using site-directed mutants. Jointly, our results provide a molecular and structural basis for the role of MAL in TLR signaling and disease protection.
Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension.
Publisher: Oxford University Press (OUP)
Date: 24-10-2019
DOI: 10.1093/CVR/CVY252
Suppressor of Cytokine Signaling (SOCS) 1 Inhibits Type I Interferon (IFN) Signaling via the Interferon α Receptor (IFNAR1)-associated Tyrosine Kinase Tyk2
Publisher: Elsevier BV
Date: 09-2011
Recombinant production of functional full-length and truncated human TRAM/TICAM-2 adaptor protein involved in Toll-like receptor and interferon signaling
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.PEP.2014.09.019
Abstract: TRAM/TICAM-2 is used by Toll-like receptor 4 (TLR4) as a bridging adaptor during the mammalian innate immune response. It recruits TRIF, another TIR domain-containing adaptor protein, to TLR4 via TIR domain interactions, which leads to the activation of transcription factors responsible for the production of type-1 interferon and cytokines. The molecular mechanisms of these dual interactions mediated by the TRAM TIR domain are not clear. To understand the molecular basis of TIR:TIR domain interactions, structural and biochemical studies of TRAM TIR domain are necessary, and require a functional soluble protein. In this paper, we report a successful purification and characterization of full-length TRAM. Because full-length TRAM likely contains unstructured regions that may be disadvantageous for structural studies, we also carried out a systematic construct design to determine the boundaries of the TRAM TIR domain. The truncated TRAM constructs were designed based on secondary structure predictions and screened by small-scale expression. Selected constructs were subjected to biophysical analyses. We show that the expressed TRAM TIR domain is functional using in vitro GST pull-down assays that demonstrate a physical interaction with the TLR4 TIR domain. We further show, by site-directed mutagenesis, that the "BB loop" regions of both the TRAM TIR domain and the TLR4 TIR domain are crucial for this physical interaction.
Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines
Publisher: Oxford University Press (OUP)
Date: 27-09-2006
Abstract: Anti-viral CD8(+) T cell responses can be induced using synthetic lipopeptides and a range of different lipid moieties have been examined in a variety of model systems and in man for this purpose. Nevertheless, only limited data exist on comparative efficacy of different lipopeptides in a single model of protection so that the optimal composition for vaccination purposes remains unknown. In this study, we examined different lipid structures from bacterial or non-bacterial sources coupled to peptides representing influenza viral epitopes recognized by CD8(+) and CD4(+) T cells. These were assessed in the context of intra-nasal (i.n.) immunization in the absence of added adjuvant. The strongest immunogens were those containing bacterially derived lipids that induced dendritic cell (DC) maturation via Toll-like receptor 2 (TLR2) binding. The number of DCs induced to mature in vitro was directly associated with the strength of the CD8(+) T cell-mediated viral clearing responses in primed mice. Mice immunized with the TLR2-binding lipopeptides showed greatly enhanced numbers of specific IFN-gamma-secreting CD8(+) T cells at the site of infection after i.n. exposure to virus, which resulted in enhanced protection of the pneumonic lung. Importantly, lipopeptide-pulsed DCs were able to induce the appropriate T cells, indicating that the self-adjuvanting effects could occur in the absence of free lipopeptide interacting with additional TLR2-bearing cells in vivo. This study defines a hierarchy of lipopeptide constructs that can program DC to prime memory CD8(+) T cells that on recall function to clear influenza virus from the infected lung.
IL-1β exacerbates disease and is a potential therapeutic target to reduce pulmonary inflammation during severe influenza A virus infection.
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/IMCB.12459
Abstract: Hyperinflammatory responses including the production of NLRP3‐dependent interleukin (IL)‐1β is a characteristic feature of severe and fatal influenza A virus (IAV) infections. The NLRP3 inflammasome has been shown to play a temporal role during severe IAV immune responses, with early protective and later detrimental responses. However, the specific contribution of IL‐1β in modulating IAV disease in vivo is currently not well defined. Here, we identified that activation of NLRP3‐dependent IL‐1β responses occurs rapidly following HKx31 H3N2 infection, prior to the onset of severe IAV disease. Mature IL‐1β was detectable in vivo in both hemopoietic and nonhemopoietic cells. Significantly, therapeutic inhibition of IL‐1β in the airways with intranasal anti‐IL‐1β antibody treatment from day 3 postinfection, corresponding to the onset of clinical signs of disease, significantly prolonged survival and reduced inflammation in the airways. Importantly, early targeting of IL‐1β from day 1 postinfection also improved survival. Together, these studies specifically define a role for IL‐1β in contributing to the development of hyperinflammation and disease and indicate that targeting IL‐1β is a potential therapeutic strategy for severe IAV infections.
The nicer side of innate immunity: Wound healing and tissue regeneration
Publisher: Elsevier BV
Date: 2017
Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity
Publisher: American Thoracic Society
Date: 08-2011
Another One Fights the Dust - Targeting the NLRP3 Inflammasome for the Treatment of Silicosis.
Publisher: American Thoracic Society
Date: 06-2022
MyD88 Is a Critical Regulator of Hematopoietic Cell-Mediated Neuroprotection Seen after Stroke
Publisher: Public Library of Science (PLoS)
Date: 04-03-2013
Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1‐F2‐dependent inflammasome activation
Publisher: Wiley
Date: 26-01-2016
DOI: 10.1038/ICB.2015.115
Activation of the NLRP3 Inflammasome by IAV Virulence Protein PB1-F2 Contributes to Severe Pathophysiology and Disease
Publisher: Public Library of Science (PLoS)
Date: 30-05-2013
IL ‐1β and IL ‐18: inflammatory markers or mediators of hypertension?
Publisher: Wiley
Date: 12-2014
DOI: 10.1111/BPH.12876
Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling
Publisher: Proceedings of the National Academy of Sciences
Date: 24-07-2017
Abstract: Toll-like receptor (TLR) signaling pathways are targeted to limit inflammation in immune cells. TLRs use adaptor proteins to drive inflammatory signaling platforms for effective microbial clearance. Here we show that MyD88 adaptor-like (MAL), an adaptor protein in TLR signaling, undergoes glutathionylation in response to LPS, driving macrophage responses to proinflammatory stimuli. We also determined the solution structure of MAL in the reduced form without disulfides, revealing a typical BB loop observed in adaptor proteins, in contrast to previously reported crystal structures. This alternate solution structure reveals the inherent flexibility of MAL, supporting the hypothesis that glutathionylation may reposition the MAL BB loop for MyD88 interaction to drive inflammation. This discovery could lead to novel approaches to target MAL glutathionylation in dysregulated TLR signaling, limiting inflammation.
IL11 activates the placental inflammasome to drive preeclampsia
Publisher: Frontiers Media SA
Date: 24-05-2023
DOI: 10.3389/FIMMU.2023.1175926
Abstract: Preecl sia is a life-threatening disorder of pregnancy unique to humans. Interleukin (IL)11 is elevated in serum from pregnancies that subsequently develop early-onset preecl sia and pharmacological elevation of IL11 in pregnant mice causes the development of early-onset preecl sia-like features (hypertension, proteinuria, and fetal growth restriction). However, the mechanism by which IL11 drives preecl sia is unknown. Pregnant mice were administered PEGylated (PEG)IL11 or control (PEG) from embryonic day (E)10-16 and the effect on inflammasome activation, systolic blood pressure (during gestation and at 50/90 days post-natal), placental development, and fetal ost-natal pup growth measured. RNAseq analysis was performed on E13 placenta. Human 1 st trimester placental villi were treated with IL11 and the effect on inflammasome activation and pyroptosis identified by immunohistochemistry and ELISA. PEGIL11 activated the placental inflammasome causing inflammation, fibrosis, and acute and chronic hypertension in wild-type mice. Global and placental-specific loss of the inflammasome adaptor protein Asc and global loss of the Nlrp3 sensor protein prevented PEGIL11-induced fibrosis and hypertension in mice but did not prevent PEGIL11-induced fetal growth restriction or stillbirths. RNA-sequencing and histology identified that PEGIL11 inhibited trophoblast differentiation towards spongiotrophoblast and syncytiotrophoblast lineages in mice and extravillous trophoblast lineages in human placental villi. Inhibition of ASC/NLRP3 inflammasome activity could prevent IL11-induced inflammation and fibrosis in various disease states including preecl sia.
Promyelocytic Leukemia Protein Interacts with the Apoptosis-associated Speck-like Protein to Limit Inflammasome Activation
Publisher: Elsevier BV
Date: 03-2014
TLR ligands of ryegrass pollen microbial contaminants enhance T h1 and T h2 responses and decrease induction of F oxp3hi regulatory T cel
Publisher: Wiley
Date: 18-01-2013
Abstract: Microbial contamination of grass pollens could affect sensitization, subsequent allergic response, and efficacy of allergen-specific immunotherapy. We investigated whether bacterial immunomodulatory substances can direct PBMC responses of allergic and nonatopic subjects against ryegrass pollen (RGP) toward Th1, Th2, or regulatory T (Treg) cells. Aqueous extracts of RGP with high or low LPS were fractionated into large and small molecular weight (MW) components by diafiltration. CFSE-labeled PBMCs from allergic and nonatopic subjects were stimulated with RGP extracts (RGPEs) and analyzed for cytokine secretion and T-cell responses. High LPS RGPE increased IFN-γ(+) Th1 and IL-4(+) Th2 effector cell induction and consistently decreased CD4(+) Foxp3(hi) Treg-cell induction. IL-10-producing T-cell frequency was unaltered, but IL-10 secretion was increased by high LPS RGPE. RGPE-stimulation of TLR-transfected cell lines revealed that high LPS pollen also contained a TLR2-ligand, and both batches a TLR9-ligand. Beta-1,3-glucans were detected in large and small MW fractions and were also T-cell stimulatory. In conclusion, coexposure to allergen and proinflammatory microbial stimuli does not convert an established Th2- into a Th1-response. Instead, proinflammatory responses are exacerbated and Foxp3(hi) Treg-cell induction is decreased. These findings show that adjuvants for specific immunotherapy should enhance Treg cells rather than target immune deviation from Th2 to Th1.
Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase-5 in human monocytes
Publisher: Wiley
Date: 14-08-2018
DOI: 10.1111/IMCB.12190
Abstract: Outer membrane vesicles (OMVs) are constitutively produced by Gram-negative bacteria both in vivo and in vitro. These lipid-bound structures carry a range of immunogenic components derived from the parent cell, which are transported into host target cells and activate the innate immune system. Recent advances in the field have shed light on some of the multifaceted roles of OMVs in host-pathogen interactions. In this study, we investigated the ability of OMVs from two clinically important pathogens, Pseudomonas aeruginosa and Helicobacter pylori, to activate canonical and noncanonical inflammasomes. P. aeruginosa OMVs induced inflammasome activation in mouse macrophages, as evidenced by "speck" formation, as well as the cleavage and secretion of interleukin-1β and caspase-1. These responses were independent of AIM2 and NLRC4 canonical inflammasomes, but dependent on the noncanonical caspase-11 pathway. Moreover, P. aeruginosa OMVs alone were able to activate the inflammasome in a TLR-dependent manner, without requiring an exogenous priming signal. In contrast, H. pylori OMVs were not able to induce inflammasome activation in macrophages. Using CRISPR/Cas9 knockout THP-1 cells lacking the human caspase-11 homologs, caspase-4 and -5,we demonstrated that caspase-5 but not caspase-4 is required for inflammasome activation by P. aeruginosa OMVs in human monocytes. In contrast, free P. aeruginosa lipopolysaccharide (LPS) transfected into cells induced inflammasome responses via caspase-4. This suggests that caspase-4 and caspase-5 differentially recognize LPS depending on its physical form or route of delivery into the cell. These findings have relevance to Gram-negative infections in humans and the use of OMVs as novel vaccines.
Toll/IL-1 Signaling Is Critical for House Dust Mite–specific Th1 and Th2 Responses
Publisher: American Thoracic Society
Date: 15-05-2009
TIR-containing adaptors in Toll-like receptor signalling
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.CYTO.2009.01.009
Abstract: While the Toll-like receptors (TLRs) are responsible for the recognition and response to pathogen ligands, increasing evidence suggests that the family of five cytosolic Toll/IL-1 receptor (TIR) adaptor proteins also play a crucial role in the specificity of the response. Genetic studies in mice, and increasingly in human polymorphic populations, have given us a greater understanding the role these adaptors play in orchestrating and coordinating the multifaceted immune response to multiple exogenous threats. Importantly, with growing evidence of the critical role TLRs play in responses to host danger signals and autoimmune disease, a more comprehensive understanding and appreciation of the role these adaptors play in disease progression may provide future targets for therapeutic intervention in human disease. Importantly, growing evidence supports the concept of pathway specific and inflammatory control by a better understanding of how these adaptors interact with other signalling mediators, where they localise within the cell and the inflammatory programs they initiate as a way of manipulating immune responses. This review deals with our current understanding of these TIR-containing adaptor proteins and how mutagenesis of specific residues and domains has increased our knowledge of their function in TLR immune responses.
The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins
Publisher: International Union of Crystallography (IUCr)
Date: 19-11-2013
DOI: 10.1107/S0907444913022385
Abstract: TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-β/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1–153 is reported. The 2.22 Å resolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTD A66M/L113M ). The structure consists of eight antiparallel helices that can be ided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-β promoter, as well as NF-κB-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation.
Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2
Publisher: American Society for Microbiology
Date: 15-10-2013
DOI: 10.1128/JVI.03099-12
Abstract: Nonstructural protein 4 (NSP4), encoded by rotavirus, exhibits various properties linked to viral pathogenesis, including enterotoxic activity. A recent study (O. V. Kavanagh et al., Vaccine 28:3106-3111, 2010) indicated that NSP4 also has adjuvant properties, suggesting a possible role in the innate immune response to rotavirus infection. We report here that NSP4 purified from the medium of rotavirus-infected Caco-2 cells triggers the secretion of proinflammatory cytokines from macrophage-like THP-1 cells and nitric oxide from murine RAW 264.7 cells. Secretion is accompanied by the stimulation of p38 and JNK mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB. NSP4 triggered the secretion of cytokines from murine macrophages derived from wild-type but not MyD88 −/− or Toll-like receptor 2 (TLR2 −/− ) mice and induced secretion of interleukin-8 (IL-8) from human embryonic kidney cells transfected with TLR2 but not TLR4. Our studies identify NSP4 as a pathogen-associated molecular pattern (PAMP) encoded by rotavirus and provide a mechanism for the production of proinflammatory cytokines associated with the clinical symptoms of infection in humans and animals.
The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms
Publisher: Oxford University Press (OUP)
Date: 23-11-2021
Abstract: TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to ergent biological responses.
Parsing the IL-37-Mediated Suppression of Inflammasome Function.
Publisher: MDPI AG
Date: 10-01-2020
DOI: 10.3390/CELLS9010178
Abstract: Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages (BMDM), and employing an in vivo endotoxemia model, we studied how IL-37 affects the expression and maturation of IL-1β and IL-18, inflammasome activation, and pyroptosis in detail. IL-37 inhibited IL-1β production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect lipopolysaccharide (LPS)-induced mRNA expression of Il18 or inflammasome components, IL-37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, we observed that IL-37 suppresses nigericin- and silica-induced ASC oligomerization/speck formation (a step in inflammasome activation and subsequent caspase-1 activation), and pyroptosis (−50%). In mice subjected to endotoxemia, IL-37 inhibited plasma IL-1β (−78% compared to wild-type animals) and IL-18 (−61%). Thus, our study adds suppression of inflammasome activity to the portfolio of anti-inflammatory pathways employed by IL-37, highlighting this cytokine as a potential tool for treating inflammasome-driven diseases.
In vivo infection model of severe influenza a virus
Publisher: Springer New York
Date: 2018
Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of the TIR domain from the Brucella melitensis TIR-domain-containing protein TcpB
Publisher: International Union of Crystallography (IUCr)
Date: 28-09-2013
Distinct noise-controlling roles of multiple negative feedback mechanisms in a prokaryotic operon system
Publisher: Institution of Engineering and Technology (IET)
Date: 03-2011
DOI: 10.1049/IET-SYB.2010.0020
Abstract: Molecular fluctuations are known to affect dynamics of cellular systems in important ways. Studies aimed at understanding how molecular systems of certain regulatory architectures control noise therefore become essential. The interplay between feedback regulation and noise has been previously explored for cellular networks governed by a single negative feedback loop. However, similar issues within networks consisting of more complex regulatory structures remain elusive. The authors investigate how negative feedback loops manage noise within a biochemical cascade concurrently governed by multiple negative feedback loops, using the prokaryotic tryptophan (trp) operon system in Escherechia coli as the model system. To the authors knowledge, this is the first study of noise in the trp operon system. They show that the loops in the trp operon system possess distinct, even opposing, noise-controlling effects despite their seemingly analogous feedback structures. The enzyme inhibition loop, although controlling the last reaction of the cascade, was found to suppress noise not only for the tryptophan output but also for other upstream components. In contrast, the Repression (Rep) loop enhances noise for all systems components. Attenuation (Att) poses intermediate effects by attenuating noise for the upstream components but promoting noise for components downstream of its target. Regarding noise at the output tryptophan, Rep and Att can be categorised as noise-enhancing loops whereas Enzyme Inhibition as a noise-reducing loop. These findings suggest novel implications in how cellular systems with multiple feedback mechanisms control noise. [Includes supplementary material].
Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia
Publisher: Proceedings of the National Academy of Sciences
Date: 09-10-2007
Abstract: Activin A is a member of the transforming growth factor-β superfamily, which we have identified as having a role in inflammatory responses. We show that circulating levels of activin increase rapidly after LPS-induced challenge through activation of Toll-like receptor 4 and the key adaptor protein, MyD88. Treatment with the activin-binding protein, follistatin, alters the profiles of TNF, IL-1β, and IL-6 after LPS stimulation, indicating that activin modulates the release of several key proinflammatory cytokines. Further, mice administered one 10-μg dose of follistatin to block activin effects have increased survival after a lethal dose of LPS, and the circulating levels of activin correlate with survival outcome. These findings demonstrate activin A's crucial role in the inflammatory response and show that blocking its actions by the use of follistatin has significant therapeutic potential to reduce the severity of inflammatory diseases.
Sculpting the immune response to infection
Publisher: Springer Science and Business Media LLC
Date: 20-06-2011
DOI: 10.1038/NI0711-579
The Single Nucleotide Polymorphism Mal-D96N Mice Provide New Insights into Functionality of Mal in TLR Immune Responses
Publisher: The American Association of Immunologists
Date: 15-04-2019
Abstract: MyD88 adaptor-like (Mal) protein is the most polymorphic of the four key adaptor proteins involved in TLR signaling. TLRs play a critical role in the recognition and immune response to pathogens through activation of the prototypic inflammatory transcription factor NF-κB. The study of single nucleotide polymorphisms in TLRs, adaptors, and signaling mediators has provided key insights into the function of the corresponding genes but also into the susceptibility to infectious diseases in humans. In this study, we have analyzed the immune response of mice carrying the human Mal-D96N genetic variation that has previously been proposed to confer protection against septic shock. We have found that Mal-D96N macrophages display reduced cytokine expression in response to TLR4 and TLR2 ligand challenge. Mal-D96N macrophages also display reduced MAPK activation, NF-κB transactivation, and delayed NF-κB nuclear translocation, presumably via delayed kinetics of Mal interaction with MyD88 following LPS stimulation. Importantly, Mal-D96N genetic variation confers a physiological protective phenotype to in vivo models of LPS-, Escherichia coli–, and influenza A virus–induced hyperinflammatory disease in a gene dosage-dependent manner. Together, these results highlight the critical role Mal plays in regulating optimal TLR-induced inflammatory signaling pathways and suggest the potential therapeutic advantages of targeting the Mal D96 signaling nexus.
The serine protease inhibitor antithrombin III inhibits LPS‐mediated NF‐κB activation by TLR‐4
Publisher: Wiley
Date: 23-11-2001
DOI: 10.1016/S0014-5793(01)03077-0
Abstract: In Drosophila, the Toll family of proteins mediates the innate immune response. Toll is activated by Spaetzle, which is generated in response to pathogens via a serine protease cascade. We wished to investigate if lipopolysaccharides (LPS) might activate Toll-like receptor (TLR) 4 via a serine protease in humans. The serpin antithrombin III (ATIII) and the thrombin inhibitor hirudin both inhibited nuclear factor (NF)-kappaB activation by LPS and Lipid A. ATIII and hirudin were also able to inhibit LPS-induced NF-kappaB activation in cells stably transfected with TLR4. These results suggest that LPS may activate a mammalian serine protease, which generates a product required for TLR4 signalling.
LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling
Publisher: Wiley
Date: 14-06-2012
DOI: 10.1038/ICB.2011.56
Abstract: Among the many inflammatory mediators induced by the prototypical inflammatory stimulus lipopolysaccharide (LPS), which signals via Toll-like receptor (TLR)-4, interleukin (IL)-6 has recently been shown to feedback and augment TLR4 signaling when overproduced in LPS hypersensitive gp130(F/F) mice. This regulation by IL-6 in gp130(F/F) mice requires hyperactivation of the latent transcription factor signal transducer and activator of transcription (STAT) 3 via the IL-6 signaling receptor subunit gp130. However, the identity of LPS/TLR4-responsive inflammatory signaling pathways and gene networks, which are modulated by IL-6 (via gp130/STAT3), and the extent to which the tissue and cellular context of this regulation contributes to LPS-induced endotoxic shock in gp130(F/F) mice, are unknown. We report here that in LPS-treated macrophages from gp130(F/F) mice, gp130 hyperactivation upregulated the LPS-induced expression of inflammatory mediators downstream of Janus kinase (JAK)/STAT, nuclear factor κ-light-chain-enhancer of activated B cells, interferon regulatory factor and c-Jun N-terminal kinase 38 mitogen-activated protein kinase pathways. Notably, however, LPS administration to bone marrow chimeras indicated that heightened LPS/TLR4 signaling in haemopoietic-derived gp130(F/F) immune cells is dispensable for the hypersensitivity of gp130(F/F) mice to LPS-induced endotoxemia. To understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers from LPS-treated gp130(F/F) mice was performed and identified 264 hepatic LPS-responsive genes, which are differentially regulated by hyperactive gp130 signaling. Collectively, the substantial transcriptional reprogramming of LPS-responsive genes in gp130(F/F) mice emphasizes non-haemopoietic gp130 signaling as a key regulator of systemic inflammatory responses during LPS-induced endotoxemia.
Mechanism of Bacterial Interference with TLR4 Signaling by Brucella Toll/Interleukin-1 Receptor Domain-containing Protein TcpB
Publisher: Elsevier BV
Date: 2000
Dangerous liaisons between interleukin-6 cytokine and toll-like receptor families: A potent combination in inflammation and cancer
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.CYTOGFR.2013.03.007
Abstract: The potent pro-inflammatory actions of members of the interleukin (IL)-6 cytokine and toll-like receptor (TLR) families have been implicated in numerous inflammatory disorders, as well as inflammation-associated cancers. It is fast becoming apparent that a hallmark of many such inflammatory-related diseases is the overlapping deregulated expression of members of each family, and the consequent augmented activation of shared signaling pathways. Here, we review the molecular basis by which the IL-6 cytokine and TLR family signaling networks are regulated, and integrate recent advances exploring the intimate cross-regulation of these two families which may provide the foundation for the future development of therapeutics to target chronic inflammation-associated diseases, including cancer.
Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection
Publisher: Wiley
Date: 19-08-2019
DOI: 10.1111/BPH.14787
Synthetic peptide analogs of intercellular adhesion molecule 1 (ICAM-1) inhibit HIV-1 replication in MT-2 cells.
Publisher: Mary Ann Liebert Inc
Date: 08-1993
Abstract: On the basis of reports demonstrating possible roles for leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), the ligand for LFA-1, in human immunodeficiency virus type 1 (HIV-1) infection, we have explored the involvement of the ICAM-1 molecule by using selected synthetic peptides derived from the protein sequence. Replication was assessed in MT-2 cells, highly susceptible to HIV infection, in the presence of four synthetic peptides derived from the ICAM-1 amino acid sequence. This cell type was chosen for the ability to form marked syncytia on infection with cell-free virus. Under the conditions used, minimal or no cytotoxicity was observed with the peptides up to concentrations of 50 micrograms/ml. A peptide corresponding to a unique region of ICAM-1, JF9 [ICAM-1(367-394, A-378)], had little effect on virus replication despite its ability to inhibit cell-cell adhesion. In contrast, an N-terminal peptide, JF7B [ICAM-1(1-23)], consistently inhibited virus replication in MT-2 cells in a dose-dependent manner, as measured by cell-free reverse transcriptase (RT) activity (up to 70% inhibition), soluble virus antigen production (up to 60% inhibition), and syncytium formation (virtually complete inhibition up to 6 days post infection). Testing of W-CAM-1 antibody, and anti-ICAM-1 antibody that inhibits cell-cell adhesion, revealed no significant inhibitory effects on RT activity, virus antigen production, and syncytium formation in HIV-1-infected MT-2 cells at a level that markedly inhibited cell-cell adhesion (10 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
The Australian Toll‐way gets the Nod—meeting report of TLROZ 2007: pattern recognition receptors in immunity and disease, Melbourne, Australia, 16–18th May 2007
Publisher: Wiley
Date: 17-07-2007
Cytokine receptors and their ligands
Publisher: Elsevier
Date: 2015
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