A5000889326- Inflammasome and immune disorders
- interferon and immune responses
- Herpesvirus Infections and Treatments
- Heme Oxygenase-1 and Carbon Monoxide
- Cytomegalovirus and herpesvirus research
- Cell death mechanisms and regulation
- Immune Response and Inflammation
- Gout, Hyperuricemia, Uric Acid
- Toxoplasma gondii Research Studies
- Bacillus and Francisella bacterial research
- Peptidase Inhibition and Analysis
- RNA regulation and disease
- IL-33, ST2, and ILC Pathways
- Toxin Mechanisms and Immunotoxins
- Erythrocyte Function and Pathophysiology
- Tryptophan and brain disorders
- Vector-Borne Animal Diseases
- Genetics and Neurodevelopmental Disorders
- Insect Resistance and Genetics
- Kawasaki Disease and Coronary Complications
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Viral-associated cancers and disorders
- Respiratory viral infections research
- Alzheimer's disease research and treatments
- Streptococcal Infections and Treatments
Janssen (Belgium)
2019-2025
Ghent University Hospital
2020-2024
Johnson & Johnson (United States)
2024
Ghent University
2010-2022
VIB-UGent Center for Inflammation Research
2016-2022
Vlaams Instituut voor Biotechnologie
2014
VIB-UGent Center for Medical Biotechnology
2014
Abstract The Nlrp3 inflammasome is critical for host immunity, but the mechanisms controlling its activation are enigmatic. In this study, we show that loss of FADD or caspase-8 in a RIP3-deficient background, not RIP3 deficiency alone, hampered transcriptional priming and posttranslational canonical noncanonical inflammasome. Deletion presence absence inhibited caspase-1 caspase-11 by stimuli Nlrc4 addition, deletion prevented maturation, positioning upstream caspase-8. Consequently, FADD-...
Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and extracellular release the inflammasome-dependent cytokines interleukin (IL)-1β IL-18, which contributes to autoinflammatory pathology. Caspases 1, 4, 5 11 trigger this regulated form necrosis by cleaving pyroptosis effector gasdermin D (GSDMD), causing its pore-forming amino-terminal domain oligomerize perforate plasma membrane. However, subcellular events that precede pyroptotic cell lysis are ill defined. In...
Despite its clinical importance in infection and autoimmunity, the activation mechanisms of NLRP1b inflammasome remain enigmatic. Here we show that deletion adaptor ASC BALB/c mice C57BL/6 macrophages expressing a functional prevents anthrax lethal toxin (LeTx)-induced caspase-1 autoproteolysis speck formation. However, ASC−/− undergo normal LeTx-induced pyroptosis secrete significant amounts interleukin (IL)-1β. In contrast, is critical for IL-1β secretion by NLRC4, NLRP3 AIM2...
Abstract The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular inflammasome sensor an important clinical target against inflammation-driven human diseases. Recent studies have elucidated its transition from closed cage to activated disk-like inflammasome, but the intermediate activation mechanism remains elusive. Here we report cryo-electron microscopy structure of NLRP3, which forms open octamer undergoes ~ 90° hinge rotation at NACHT...
Significance Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by more than 310 mutations in the gene MEFV , which encodes Pyrin. Pyrin recently was shown to trigger inflammasome activation response Rho GTPase-modifying bacterial toxins. Here we report that Clostridium difficile infection and intoxication with its enterotoxin TcdA engage inflammasome. Moreover, of inflammasome, but not other inflammasomes, hampered microtubule-depolymerizing drugs mouse humans....
The caspase activation and recruitment domain (CARD)-based inflammasome sensors NLRP1b NLRC4 induce caspase-1-dependent pyroptosis independent of the adaptor ASC. Here, we show that trigger caspase-8-mediated apoptosis as an alternative cell death program in caspase-1−/− macrophages intestinal epithelial organoids (IECs). caspase-8 FADD was recruited to ASC specks, which served cytosolic platforms for NLRP1b/NLRC4-induced apoptosis. We further found caspase-1 protease activity dominated over...
Significance The Nlrc4 inflammasome is critical for clearing bacterial infections and activating mutations in NLRC4 cause autoinflammation patients. Here, we used genetic biochemical approaches to show that Ser533 phosphorylation by flagellin of Salmonella Typhimurium Yersinia enterocolitica occurs upstream Naip5 detection flagellin, ASC speck formation caspase-1 activation. We further showed Helicobacter pylori triggered robust but failed elicit activation agreement with the differential...
Pyroptosis has emerged as a key mechanism by which inflammasomes promote host defense against microbial pathogens and sterile inflammation. Gasdermin D (GSDMD)-mediated cell lysis is hallmark of pyroptosis, but our understanding death signaling during pyroptosis fragmented. Here, we show that independently GSDMD-mediated plasma membrane permeabilization, inflammasome receptors engage caspase-1 caspase-8, both redundantly activation apoptotic executioner caspase-3 caspase-7 in pyroptotic...
Activating germline mutations in the human inflammasome sensor NLRP1 causes palmoplantar dyskeratosis and susceptibility to Mendelian autoinflammatory diseases. Recent studies have shown that cytosolic serine dipeptidyl peptidases DPP8 DPP9 suppress activation upstream of CARD8 keratinocytes peripheral blood mononuclear cells. Moreover, pharmacological inhibition DPP8/DPP9 protease activity was induce pyroptosis murine C57BL/6 macrophages without eliciting other hallmark responses. Here, we...
NLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1β, and pyroptosis, regulated cell death. Mounting evidence associates excessive activation neurodegenerative conditions, such as Alzheimer's Parkinson's diseases. Thus, inhibitors could potentially provide therapeutic benefit these disorders. We describe here the evolution of relying on pyridazine-based motif their key interactions with NLRP3. A Cryo-EM...
Background Several alphaherpesviruses, including herpes simplex virus 1 (HSV-1) and pseudorabies (PRV), establish lifelong latency in neurons of the trigeminal ganglion (TG). Although it is thought that efficient establishment alphaherpesvirus based on a subtle interplay between virus, immune system, not clear which components are major importance for latency. Methodology/Principal Findings Here, using an vitro model enables natural route infection, we show interferon alpha (IFNalpha) has...
Significance Anthrax is a deadly infection caused by exposure to Bacillus anthracis bacteria. lethal toxin (LeTx) has long been recognized as major determinant of anthrax, which paralyzes the host’s immune defenses killing off macrophages. Despite importance macrophage cytotoxicity in anthrax pathogenesis, signaling pathways underlying cell death B. -infected macrophages are poorly understood. This study shows that with live or LeTx intoxication sensitizes TNF-dependent NLRP3 inflammasome...
We have previously shown that the porcine alphaherpesvirus pseudorabies virus (PRV) efficiently interferes with phosphorylation of eukaryotic translation initiation factor eIF2α. Inhibition eIF2α has been reported earlier for closely related herpes simplex 1 (HSV-1) through its ICP34.5 and US11 proteins. PRV, however, does not encode an or orthologue. Assays using cycloheximide, UV-inactivated phosphonoacetic acid (PAA) showed de novo expression one more (immediate) early viral protein(s) is...
Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid deposition and formation neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part innate immune system, has been implicated neuropathology both preclinical amyloid tau transgenic models. Activation NLRP3 pathway involves an initial priming step, which increases expression Nlrp3 interleukin (IL)-1β, followed by assembly inflammasome...