A5081858211- Inflammasome and immune disorders
- Cell death mechanisms and regulation
- interferon and immune responses
- Immune Response and Inflammation
- Immune cells in cancer
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Kawasaki Disease and Coronary Complications
- Phagocytosis and Immune Regulation
- Immune responses and vaccinations
- Immune Cell Function and Interaction
- Heme Oxygenase-1 and Carbon Monoxide
- RNA Interference and Gene Delivery
- Biomedical Research and Pathophysiology
- T-cell and B-cell Immunology
- Cholesterol and Lipid Metabolism
- Autoimmune and Inflammatory Disorders Research
- Vasculitis and related conditions
- Brucella: diagnosis, epidemiology, treatment
- Calpain Protease Function and Regulation
- Toxoplasma gondii Research Studies
- Antimicrobial Resistance in Staphylococcus
- Protein Kinase Regulation and GTPase Signaling
- Escherichia coli research studies
- Hippo pathway signaling and YAP/TAZ
- Calcium signaling and nucleotide metabolism
University of York
2021-2025
Biomedical Research Institute
2023-2025
The University of Queensland
2014-2024
University of Lausanne
2019-2020
Université de Sherbrooke
2010-2012
Neutrophils form gasdermin D pores and expel antimicrobial neutrophil extracellular traps to defend against cytosolic bacteria.
Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate dimerization and autoprocessing. Previous studies with recombinant protein identified a tetramer composed two p20 p10 subunits (p20/p10) as an active species. In this study, we report in cell, dominant species dimers elicited by inflammasomes fact full-length p46...
Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase‐4 and caspase‐5. When activated, these trigger pyroptotic cell death caspase‐1‐dependent IL‐1β production; however the mechanism underlying this process is not yet confirmed. We now show a specific NLRP3 inhibitor, MCC950, prevents caspase‐4/5‐dependent production elicited by transfected LPS. Given both caspase‐5 can it possible proteins exhibit some degree of redundancy. Therefore, we generated human monocytic...
IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute secretion from inflammasome-activated macrophages caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of pyroptotic and non-pyroptotic cells, precise functions therein, are unresolved. Here, we show that, while efficient early endogenous primary myeloid cells in vitro GSDMD, later release vivo proceeds independently GSDMD. maturation is sufficient for slow,...
Abstract The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds oligomerizes caspase-4, the pathway is thought proceed without dedicated sensors or an platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for by Salmonella upon delivery of LPS. GBP1 associates with surface seconds after escape from their vacuole, initiating...
Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens immune pathology in autoinflammatory diseases. assemble when an inflammasome scaffold protein senses activating signal forms a signaling platform with the adaptor ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes nucleators (such as NLRP3) also NLRP12, which is genetically linked familial disorders resemble diseases caused by gain-of-function NLRP3 mutants...
During apoptosis, hundreds of proteins are cleaved by caspases, most them the executioner caspase-3. However, caspase-7, which shares same substrate primary sequence preference as caspase-3, is better at cleaving poly(ADP ribose) polymerase 1 (PARP) and Hsp90 cochaperone p23, despite a lower intrinsic activity. Here, we identified key lysine residues (K 38 KKK) within N-terminal domain caspase-7 critical elements for efficient proteolysis these two substrates. Caspase-7's binds PARP improves...
Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays lysis, indicating that caspase-1 controls alternative pathways. Here, we show in absence of GSDMD, activates apoptotic initiator and executioner caspases triggers rapid progression into secondary necrosis. GSDMD-independent required direct caspase-1–driven truncation Bid generation caspase-3 p19/p12 either caspase-8 or caspase-9....
Caspase-11 is a cytosolic sensor and protease that drives innate immune responses to the bacterial cell wall component, LPS. provides defence against Gram-negative bacteria; however, excessive caspase-11 contribute murine endotoxic shock. Upon sensing LPS, assembles higher order structure called non-canonical inflammasome enables activation of function, leading gasdermin D cleavage death. The mechanism by which acquires function is, poorly defined. Here, we show dimerization necessary...
The noncanonical inflammasome is a signalling complex critical for cell defence against cytosolic Gram-negative bacteria. A key step in the human pathway involves unleashing proteolytic activity of caspase-4 within this complex. Caspase-4 induces inflammatory responses by cleaving gasdermin-D (GSDMD) to initiate pyroptosis; however, molecular mechanisms that activate and govern its capacity cleave substrates remain poorly defined. Caspase-11, murine counterpart caspase-4, acquires protease...
Abstract Inflammasomes are signaling hubs that activate inflammatory caspases to drive cytokine maturation and cell lysis. Inflammasome activation by Salmonella Typhimurium infection or Salmonella-derived molecules is extensively studied in murine myeloid cells. Salmonella-induced inflammasome human innate immune cells, however, poorly characterized. Here, we show mutation inactivate the pathogenicity island-2 type III secretion system (SPI2 T3SS) potentiates S. Typhimurium-induced responses...
Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Despite the advances study TII-mediated activity, impact TII on orchestration tumour setting requires further elucidation. Here, we investigated whether macrophage can be modulated through induction TII.To this end, mice were...
Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Despite the advances study TII-mediated activity, impact TII on orchestration tumour setting requires further elucidation. Here, we investigated whether macrophage can be modulated through induction TII.To this end, mice were...
Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by caspase-1 (CASP1) protease, allow inflammation resolve and reinstate tissue homeostasis. It is unknown how CASP1 terminates its activity in vivo. Here, we use a knock-in mouse model which CARD domain linker (CDL) mutated prevent self-cleavage (Casp1.CDL mice) show that CDL autoproteolysis We examined these mice under homeostatic conditions response major physiological challenges. In brain, mutation...
Abstract The mammalian inhibitor of apoptosis proteins (IAPs) are key regulators cell death and inflammation. A major function IAPs is to block the formation a death–inducing complex, termed ripoptosome, which can trigger caspase-8–dependent or caspase-independent necroptosis. Recent studies report that upon TLR4 TNF receptor 1 (TNFR1) signaling in macrophages, ripoptosome also induce NLRP3 inflammasome IL-1β maturation. Whether neutrophils have capacity assemble activation during TNFR1...
Our epithelium represents a battle ground against variety of insults including pathogens and danger signals. It encodes multiple sensors that detect respond to such insults, playing an essential role in maintaining defending tissue homeostasis. One key set defense mechanisms is our inflammasomes which drive innate immune responses including, sensing responding pathogen attack, through the secretion pro‐inflammatory cytokines cell death. Identification physiologically relevant triggers for...
Uropathogenic Escherichia coli (UPEC) is the major cause of urinary tract infections (UTIs). The multidrug-resistant E. sequence type 131 (ST131) clone a serious threat to human health, yet its effects on immune responses are not well understood. Here we screened panel ST131 isolates, finding that only strains expressing toxin hemolysin A (HlyA) killed primary macrophages and triggered maturation inflammasome-dependent cytokine IL-1β. Using representative strain, requirement for hlyA gene in...
During apoptosis, initiator caspases (8, 9 and 10) activate downstream executioner (3, 6 7) by cleaving the IDC (interdomain connector) at two sites. Here, we demonstrate that both activation sites, site 1 2, of caspase 7 are suboptimal for 8 in cellulo, vitro using recombinant proteins kinetics. Indeed, when sites replaced with preferred motifs recognized either or 9, found an up to 36-fold improvement activation. Moreover, cleavage is 2 because its location within IDC, since swapping does...
Caspase-1 location in cells has been studied with fluorochrome-labeled inhibitors of caspase-1 (FLICA reagents). We report that FLICA reagents have limited cell-membrane permeability. This impacts experimental design as intact membranes, including knockout cells, are not appropriate controls for inflammasome-induced gasdermin D membrane pores. is an inflammatory initiator caspase responsible the maturation pro-inflammatory cytokines IL-1β and IL-18 pyroptotic cell death. Inhibitors important...