Human Th17 cells engage gasdermin E pores to release IL-1alpha upon NLRP3 inflammasome activation
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PROVIDER: PRJNA893842 | ENA |
REPOSITORIES: ENA
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Project description:Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the innate danger signal IL-1. This property was restricted to a subset of human Th17 cells with antigen specificity for C. albicans and was regulated by a T-cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1 form. This equipped human Th17 cells with a so far overlooked effector function that contributes to the clearance of C. albicans. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells and thus suggests new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in anti-fungal host defense.
2022-10-24 | GSE214292 | GEO
Project description:Human Th17 cells engage gasdermin E pores to release IL-1a upon NLRP3 inflammasome activation [Array]
| PRJNA885796 | ENA
Project description:Human Th17 cells engage gasdermin E pores to release IL-1a upon NLRP3 inflammasome activation [RNA-seq]
| PRJNA885482 | ENA
Project description:Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells with antigen specificity for C. albicans and was regulated by a T-cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1a form. This equipped human Th17 cells with a so far overlooked effector function that contributes to the clearance of C. albicans. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells and thus suggests new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in anti-fungal host defense.
2022-10-24 | GSE214519 | GEO
Project description:Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells with antigen specificity for C. albicans and was regulated by a T-cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1a form. This equipped human Th17 cells with a so far overlooked effector function that contributes to the clearance of C. albicans. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells and thus suggests new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in anti-fungal host defense.
2022-10-24 | GSE214475 | GEO
Project description:S100A8/A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is still elusive. We report here that E-selectin-induced rapid S100A8/A9 release during inflammation occurs in a NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton?s tyrosine kinase dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel KV1.3 mediates ASC oligomerization. This is followed by caspase-1 cleavage and downstream activation of pore forming gasdermin D, enabling cytosolic S100A8/A9 to be released. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death, but is a transient process involving activation of the ESCRT-III membrane repair machinery. These findings do not only elucidate the molecular mechanisms of controlled S100A8/A9 release but also identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation.
2023-10-25 | PXD041652 | Pride
Project description:Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.
| S-EPMC5539988 | biostudies-literature
Project description:Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid cells in the tumor milieu remains elusive. To resolve this complexity, scRNA-seq of human head & neck carcinoma identified distinct inflammasome complex genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, NLRP3 sensor and downstream effector IL-1β transcripts were enriched in multiple monocytic and macrophage subtypes in the TME. In vivo, we showed that NLRP3, and not AIM2, phenocopied the caspase-1/IL-1β dependent tumor progression. Paradoxically, we found that myeloid-intrinsic caspase-1 signaling within the TME increased myeloid survival without significant intratumoral trafficking as would be predicted from their canonical pyroptotic function. Mechanistically, this myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. When we probed for the tumor intrinsic factors that regulated NLRP3/IL-1β signaling, we found that mononuclear phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3 dependent inflammasome signaling to drive IL-1β secretion and to promote tumor growth. Dynamic RNA velocity analysis of the single cell transcriptomic dataset showed a strong directional flow from efferocytosis gene-sethigh macrophages to an inflammasome gene-sethigh macrophage population. Cumulatively, we provide a novel inflammasome signaling axis between tumor apoptosis and myeloid cells that characterizes chronic inflammation induced malignancy.
2022-04-13 | GSE200560 | GEO
Project description:Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway.
| S-EPMC6459836 | biostudies-literature
Project description:We found that TLS can work as a PGC-1alpha cofactor and this assay was carried out to test the functional dependency of TLS on PGC-1alpha on a whole genome scale
2013-07-26 | GSE23242 | GEO