ORCID Profile
0000-0003-1995-5424
Current Organisations
Beatson Institute for Cancer Research
,
University of Birmingham
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Publisher: Elsevier BV
Date: 07-2020
Publisher: Oxford University Press (OUP)
Date: 2022
Abstract: In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. Nr4a3-Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that Nr4a1/Nur77 may be a more sensitive gene to distal TCR signals compared to Nr4a3, so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69+ lymphoid T cells are enriched for FT Blue+ Red+ T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of Nr4a1 to lower TCR signal strengths.
Publisher: Wiley
Date: 15-12-2012
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 13-01-2023
DOI: 10.1101/2023.01.12.523780
Abstract: Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice ( Nr4a3-Tocky-Ifng-YFP ) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced T CM formation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1038/NATURE08530
Publisher: Oxford University Press (OUP)
Date: 07-06-2019
DOI: 10.1111/CEI.13329
Abstract: Maintaining homoeostatic host–microbe interactions is vital for host immune function. The gut microbiota shapes the host immune system and the immune system reciprocally shapes and modifies the gut microbiota. However, our understanding of how these microbes are tolerated and how in idual, or communities of, gut microbes influence host function is limited. This review will focus on metabolites as key mediators of this complex host–microbe relationship. It will look at the central role of epithelial metabolism in shaping the gut microbiota, how microbial metabolites influence the epithelium and the mucosal and peripheral immune system, and how the immune system shapes microbial composition and metabolism. Finally, this review will look at how metabolites are involved in cross-talk between different members of the microbiota and their role during infections.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.SMIM.2011.01.011
Abstract: The gut microbiota has recently been recognized for its role in immune regulation, and changes in gut microbiota may be the basis for an increased incidence of autoimmune diseases and asthma in developed countries. Beneficial microbes produce factors that are distributed systemically, and therefore can influence peripheral inflammatory responses. Such symbiosis factors are important for the control and resolution of inflammation and autoimmune diseases. Here we discuss immune regulation by recently identified symbiosis factors and how certain environmental factors favor their production and influence the composition of the gut microflora.
Publisher: Wiley
Date: 25-05-2015
DOI: 10.1002/ART.39107
Abstract: Host–microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin‐1β (IL‐1β) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite‐sensing receptor GPR43 in regulating inflammation in a murine model of gout. Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL‐1β and CXCL1. These parameters were greatly decreased in germ‐free mice, mice treated with antibiotics, and GPR‐43–deficient mice. Recolonization or administration of acetate to germ‐free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ‐free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR‐43–deficient mice. Treatment of germ‐free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. In the absence of microbiota, there is decreased production of short‐chain fatty acids that are necessary for adequate inflammasome assembly and IL‐1β production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host's ability to respond to an inflammasome‐dependent acute inflammatory stimulus outside the gut.
Publisher: Rockefeller University Press
Date: 02-03-2015
DOI: 10.1084/JEM.20140474
Abstract: NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6Δ/Δ), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6Δ/Δ mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6Δ/Δ mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6Δ/Δ mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6Δ/Δ mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2011
DOI: 10.1038/NI0111-5
Abstract: The fields of immunology, microbiology, nutrition and metabolism are rapidly converging. Here we expand on a diet-microbiota model as the basis for the greater incidence of asthma and autoimmunity in developed countries.
Publisher: Life Science Alliance, LLC
Date: 07-03-2022
Abstract: Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1–mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1 −/− mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.
Publisher: Wiley
Date: 28-03-2022
DOI: 10.1111/IMM.13472
Abstract: In CD4 + T helper cells, the active form of vitamin D 3 , 1,25‐dihydroxyvitamin D 3 (1,25D) suppresses production of inflammatory cytokines, including interferon‐gamma (IFN‐γ), but the mechanisms for this are not yet fully defined. In innate immune cells, response to 1,25D has been linked to metabolic reprogramming. It is unclear whether 1,25D has similar effects on CD4 + T cells, although it is known that antigen stimulation of these cells promotes an anabolic metabolic phenotype, characterized by high rates of aerobic glycolysis to support clonal expansion and effector cytokine expression. Here, we performed in‐depth analysis of metabolic capacity and pathway usage, employing extracellular flux and stable isotope‐based tracing approaches, in CD4 + T cells treated with 1,25D. We report that 1,25D significantly decreases rates of aerobic glycolysis in activated CD4 + T cells, whilst exerting a lesser effect on mitochondrial glucose oxidation. This is associated with transcriptional repression of Myc, but not repression of mTOR activity under these conditions. Consistent with the modest effect of 1,25D on mitochondrial activity, it also did not impact CD4 + T‐cell mitochondrial mass or membrane potential. Finally, we demonstrate that inhibition of aerobic glycolysis by 1,25D substantially contributes to its immune‐regulatory capacity in CD4 + T cells, since the suppression of IFN‐γ expression was significantly blunted in the absence of aerobic glycolysis. 1,25‐Dihydroxyvitamin D 3 (1,25D) suppresses the production of inflammatory cytokines such as interferon‐gamma (IFN‐γ) by CD4 + T cells, but the underpinning mechanisms are not yet fully defined. Here, we identify that 1,25D inhibits aerobic glycolysis in activated CD4 + T cells, associated with decreased c‐Myc expression. This mechanism appears to substantially contribute to the suppression of IFN‐γ by 1,25D, since this is significantly blunted in the absence of aerobic glycolysis.
Publisher: Portland Press Ltd.
Date: 02-12-2021
DOI: 10.1042/BST20210365
Abstract: The gut relies on the complex interaction between epithelial, stromal and immune cells to maintain gut health in the face of food particles and pathogens. Innate sensing by the intestinal epithelium is critical for maintaining epithelial barrier function and also orchestrating mucosal immune responses. Numerous innate pattern recognition receptors (PRRs) are involved in such sensing. In recent years, several Nucleotide-binding-domain and Leucine-rich repeat-containing receptors (NLRs) have been found to partake in pathogen or damage sensing while also being implicated in gut pathologies, such as colitis and colorectal cancer (CRC). Here, we discuss the current literature focusing on NLR family apoptosis inhibitory proteins (NAIPs) and other NLRs that have non-inflammasome roles in the gut. The mechanisms behind NLR-mediated protection often converges on similar signalling pathways, such as STAT3, MAPK and NFκB. Further understanding of how these NLRs contribute to the maintenance of gut homeostasis will be important for understanding gut pathologies and developing new therapies.
Publisher: American Society for Clinical Investigation
Date: 28-10-2021
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2019
DOI: 10.1101/741686
Abstract: Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. The intestinal epithelium is the natural route of infection for Salmonella and thus harbors innate immune defenses which protect against infection. Attenuated strains of Salmonella enterica serovar Typhimurium ( S Tm) have commonly been used in mouse models of BCT, largely with the use of xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using mouse models of intestinal tumorigenesis and tumor organoid cultures to assess the effectiveness and mechanisms of treatment with aromatase A-deficient S Tm ( STm Δ aroA ). STm Δ aroA delivered by oral gavage could significantly reduce tumor burden and tumor load in both a colitis-associated colon cancer model (CAC) and in a spontaneous intestinal cancer model, Apc min/+ mice. STm Δ aroA colonization of tumors caused alterations in transcription of mRNAs associated with epithelial–mesenchymal transition as well as metabolic and cell cycle-related transcripts. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STm Δ aroA -treated tumors, suggesting STm Δ aroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro demonstrated that STm Δ aroA can directly affect the tumor epithelium with alterations in transcripts and metabolites similar to in vivo -treated tumors. Thereby, we demonstrate that bacterial cancer therapy is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium, which have not previously been appreciated. Attenuated Salmonella enterica serovar Typhimurium can home to gastrointestinal tumors and directly affect the tumor epithelium, inducing transcriptional and metabolic changes that lead to reduced tumor burden in mice.
Publisher: American Physiological Society
Date: 15-08-2014
DOI: 10.1152/AJPCELL.00306.2013
Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.
Publisher: Public Library of Science (PLoS)
Date: 08-2013
Publisher: American Society for Clinical Investigation
Date: 19-03-2018
DOI: 10.1172/JCI94956
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.CHOM.2014.07.001
Abstract: The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.
Publisher: Elsevier BV
Date: 08-2015
Abstract: While the functional importance of inflammasomes in blood-derived cell types is well established, it remains poorly understood how inflammasomes in nonhematopoietic cells contribute to mucosal immunity. Recent studies have revealed functional roles of inflammasomes - particularly NAIP/NLRC4, NLRP6, and noncanonical caspase-4 (caspase-11) - within epithelial cells of the gut in mucosal immune defense, inflammation, and tumorigenesis. Here, we review and discuss these findings in the broader context of tissue compartment-specific mucosal immunity. We propose several models whereby activities of the intestinal epithelial inflammasomes converge on mechanisms to remove compromised epithelial cells, maintain host-microbiota mutualism, and communicate with immune cells of the underlying lamina propria.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2018
End Date: 2020
Funder: Wellcome Trust
View Funded ActivityStart Date: 2012
End Date: 2014
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2010
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2025
Funder: Cancer Research UK
View Funded Activity