Toutes les informations :
Abstract:
Inflammasomes are intracellular multi-protein complexes that play essential functions in immunity against pathogens. Specifically, inflammasomes both promote a regulated form of cell death termed pyroptosis and trigger the release of the key inflammatory cytokines interleukin (IL)-1β and IL-18, two important processes in controlling microbial infections. Because of their involvement in various pathophysiological conditions, our understanding of inflammasomes has generated an ever-growing interest in the scientific and medical communities over the last 20 years. Yet, most of this knowledge comes either from the use of rodent models, which may lack the specific structural and functional characteristics of human inflammasomes, or from the use of immune cells, which express a wide range of inflammasomes but lack inflammasomes specifically enriched in non-immune cells.
In this context, I will discuss about novel findings on the crucial immune function of the human NLRP1 inflammasome, highly expressed in airway, skin and corneal epithelia, in response to a broad range of infections but also environmental threats that converge to a specific stress pathway, the ribotoxic stress response. Specifically I will adress our very recent findings that unexpectedely link dna damage and ribotoxic stress-induced nlrp1 inflammasome response upon chemotherapy and microbial genotoxin exposure.
Abstract:
Prokaryotic pore-forming toxins drive inflammasome activation and pyroptosis through K+-dependent activation of the canonical NLRP3/caspase-1/gasdermin D signaling axis. In this study, we hypothesized that perforin, a eukaryotic pore-forming protein released into the lytic synapse by antigen-specific cytotoxic T lymphocytes (CTLs) upon cognate antigen recognition, mimics the pro-pyroptotic activity of ancestral pore-forming toxins, complementing its role as a conduit for granzymes. Utilizing imaging and molecular approaches, we demonstrate that perforation of target cells upon CTL attack elicits swift K+ efflux followed by NLRP3-dependent activation of proinflammatory caspase-1 and its major substrate, the pyroptotic executioner gasdermin D (GSDMD). Acute target cell death upon CTL attack is gasdermin-dependent and demonstrates morphological and molecular features of pyroptosis, including pyroptotic body formation, cell bloating, plasma membrane rupture, and release of intracellular contents; by contrast, sustained interaction with CTLs unmasks a delayed apoptotic phenotype in the remaining target cells. Perforation of target cells by soluble perforin is sufficient to trigger rapid K+ efflux, caspase-1 activation, and pyroptosis. Our results reveal a novel mechanism for engagement of pyroptotic machinery upon CTL attack, in which perforin itself can autonomously engage programmed cell death (PCD), highlighting the complexity and diversity of the CTL lytic arsenal.
Abstract:
Pyroptosis is a highly inflammatory form of regulated cell death driven by pore-forming gasdermin (GSDM) proteins. Following proteolytic activation, GSDMs form oligomeric pores that promote plasma membrane rupture (PMR) and amplify the inflammatory response. Canonical pyroptosis is initiated by inflammasome complexes, which recruit and mature caspase-1 to activate GSDMD. Independently of the inflammasome, GSDME can transition apoptosis to pyroptosis following cleavage by caspase-3. A subset of HIV[+] patients experience progressive cognitive impairment and neurodegeneration (NeuroHIV) driven by infection of brain myeloid cells. However, the mechanisms which underlie neuronal injury remain uncertain. We hypothesized that the inflammasome-pyroptosis axis (IPA) in neurons directly mediates HIV-associated neurodegeneration. Examination of primary human neural cultures revealed GSDMD is restricted to glial cells, whereas neurons selectively express GSDME. Neurons exposed to HIV viral protein R (Vpr), an established NLRP3 inflammasome stimulus, showed substantial neurite retraction and PMR with activation of caspases-1, -3 and GSDME. Genetic knockdown of NLRP3, caspase-1, or GSDME significantly reduced neuronal PMR. Furthermore, caspase-1 inhibition limited caspase-3/GSDME cleavage and neurite degradation, suggesting that inflammasome signalling initiates neuronal pyroptosis. Direct activation of caspase-1 using an optogenetic approach verified these findings, resulting in rapid activation of the caspase-3/GSDME axis, PMR and cell death morphologically consistent with pyroptosis. Furthermore, analysis of cortical brain tissues from persons with NeuroHIV and in an associated macaque model (NeuroSIV) revealed GSDME cleavage and markers of neuronal pyroptosis. Our findings demonstrate neuronal IPA signalling with downstream GSDME activation can directly contribute to HIV-associated neurodegeneration.
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