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Casp8- and Casp11-dependent gene expression in ileal mucosa of LPS-challenged male mice

ABSTRACT: The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin d. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate LPS shock independent of caspase-8 or caspase-11. Both proteases had to be present to support tissue injury, dependent upon TNF and interferon , first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock, but collaborated to amplify the inflammatory signals associated with tissue injury. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independent of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization during inflammatory signaling in vivo where cytokines execute diverse cell death pathways and tissue damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE115094 | GEO | 2018/08/07

REPOSITORIES: GEO

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Mouse macrophages from bone marrow treatment

Project description:The noncanonical inflammasome induced by intracellular lipopolysaccharide (LPS) leads to caspase-11-dependent pyroptosis, which is critical for induction of endotoxic shock in mice. However, the signaling pathway downstream of caspase-11 is unknown. We found that cytosolic LPS stimulation induced caspase-11-dependent cleavage of the pannexin-1 channel followed up by ATP release, which in turn activated the purinergic P2X7 receptor to mediate cytotoxicity. In the absence of P2X7 or pannexin-1, pyroptosis induced by cytosolic LPS was abrogated. Cleavage of pannexin-1 required the catalytic activity of caspase-11 and was essential for ATP release and P2X7-mediated pyroptosis. Priming the caspase-11 pathway in vivo with LPS or Toll-like receptor-3 (TLR3) agonist resulted in high mortality in wild-type mice after secondary LPS challenge, but not in Casp11(-/-), Panx1(-/-), or P2x7(-/-) mice. These results reveal a critical role for pannexin-1 and P2X7 downstream of caspase-11 for pyroptosis and susceptibility to sepsis induced by the noncanonical inflammasome. Research is published, core data not used but project description is relevant: http://www.sciencedirect.com/science/article/pii/S1074761315004094

2015-06-05 | ST000174 | MetabolomicsWorkbench

Inflammatory macrophage-derived extracellular vesicles trigger the non-canonical pyroptosis pathway in chondrocytes leading to cartilage catabolism and degeneration in osteoarthritis

Project description:The severity of osteoarthritis (OA) and cartilage degeneration are highly correlated with the development of synovitis, which is mediated by the activity of inflammatory macrophages. A better understanding of intercellular communication between inflammatory macrophages and chondrocytes should aid in the discovery of novel therapeutic targets. Here, we explored the pathological role of inflammatory macrophage-extracellular vesicles (EVs) in cartilage degeneration. Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages and the resulting EVs (M-LPS EVs) were harvested for chondrocyte stimulation and intraarticular injection in a mouse model. This stimulation resulted in increased catabolism of chondrocytes and cartilage degeneration. Consistently, RNA-seq analyses of stimulated chondrocytes indicated that upregulated genes are mainly categorized into apoptotic process and TNF-signaling pathway which suggests the induction of apoptotic process. These chondrocytes exhibited a significant elevation in the expression of pyroptosis-related molecules that were correlated with the expression of chondrocyte catabolic factors. The disruption of caspase-11 significantly alleviated pyroptotic and catabolic processes in stimulated chondrocytes and the pathological changes in collagenase-induced OA model. Our results provide a new insight into the pathological mechanisms of OA and suggest that non-canonical pyroptosis signaling in chondrocytes represents an attractive therapeutic target for future treatment.

2023-09-20 | GSE199193 | GEO

Differences in gene expression between WT and IRF2 KO cells

Project description:Gasdermin-D (GSDMD) is cleaved by caspase-1/4/11 in response to canonical and non-canonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms membrane pores, resulting in IL-1Î² secretion, pyroptotic cell death and inflammatory pathologies including periodic fever syndromes and septic shock â a plague on modern medicine. The transcriptional machinery that drives the expression of GSDMD is unknown. Here we show that IRF2, a member of the interferon-regulatory factor (IRF) family, is essential for the transcriptional activation of GSDMD. A forward genetic screen with ethyl-N-nitrosourea (ENU)-mutagenized mice unequivocally linked IRF2 to inflammasome signaling. Indeed, GSDMD transcript levels were highly attenuated in Irf2â/â macrophages upon Irf2 deficiency in macrophages, endothelial cells, and multiple organs, corresponding to attenuated IL-1Î² secretion and inhibited pyroptosis. Mechanistically, IRF2 binds a previously uncharacterized site within the GSDMD promoter to directly drive GSDMD transcription for execution of pyroptosis in response to canonical and non-canonical inflammasome activation. Our data illuminate a prominent transcriptional mechanism for the expression of GSDMD, a key mediator of inflammatory pathologies.

2019-05-21 | GSE130195 | GEO

CASP8 C362A KI MLKL KO e16.5 intestine RNAseq

Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumor necrosis factor receptor 1) 1, and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like) 2-4. Mice lacking caspase-8 display MLKL-dependent embryonic lethality 4, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable 4, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that inactive caspase-8 activates pyroptosis in MLKL-deficient intestinal epithelial cells around embryonic day 18, triggering the formation of ASC specks. Accordingly, intestinal atrophy and perinatal lethality in Casp8C362A/C362A Mlkl-/- mice was prevented by loss of caspase-1. In transfection studies, inactive caspase-8 mutants C362A or C362S were found in both the triton X-100 insoluble and soluble fractions, whereas wild-type caspase-8 existed only in the soluble fraction. Moreover, inactive caspase-8 shifted co-transfected ASC into the insoluble fraction, whereas wild-type caspase-8 did not. Thus, a defense mechanism is revealed that would allow intestinal epithelial cell death in the face of pathogens expressing virulence factors to inhibit caspase-8-dependent apoptosis and necroptosis.

2019-09-20 | GSE125625 | GEO

Clustering of Tir during E. coli infection affects Ca2+-dependent LPS internalisation leading to activation of pyroptosis in intestinal epithelial cells

Project description:Clustering of the Enteropathogenic (EPEC) Escherichia coli Tir effector, induced by its binding to Intimin, leads to pyroptotic cell death in macrophages. The effect of Tir clustering following EPEC infection of epithelial cells remains unexplored. In this study, we show that EPEC induces pyroptosis in an intestinal epithelial cell (IEC) line, in a Tir-dependent but actin polymerisation-independent manner, which was enhanced by priming with IFNγ. Mechanistically, Tir clustering induces rapid Ca2+ influx, which promotes internalisation of LPS, followed by activation of caspase-4. Chelation of extracellular Ca2+ or knockdown of caspase-4 inhibited cell death upon EPEC infection, whereas ATP-induced extracellular Ca2+ influx had the opposite effect confirming the regulatory role of calcium in the pathway. Additionally, IEC lines with low endogenous expression of caspase-4 were resistant to EPEC-induced cell death. We reveal a novel mechanism of LPS internalisation, following infection with an extracellular pathogen, leading to pyroptosis in IECs.

2020-10-28 | PXD018763 | Pride

Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair

Project description:Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin 1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system where macrophages are induced to undergo pyroptosis without IL-1β/⍺ release (denoted Pyro-1), we uncover unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation, and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, as well as faster wound closure in vitro, and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that PGE2 synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation, and COX2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on Gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome 1 Mehrotra et al., Page No. possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.

2024-04-07 | GSE262847 | GEO

IFNγ sensitizes macrophages to pathogen ligand killing via a unique caspase-8 and mitochondrial cell death pathway licensed by nitric oxide

Project description:Caspase-8 modulates TLR-induced gene transcription, which is only partially dependent on caspase-8 catalytic activity. Moreover, The slow kinetics of IFNγ and LPS-induced BMDM killing offers the possibility that transcriptional responses may contribute to cell death activation. We performed 3' mRNA-sequencing to examine whether caspase-8 might contribute, at least in part, to IFNγ and LPS-triggered macrophage death via its transcriptional role. We found that caspase-8-mediated transcriptional re-programming of BMDMs. Importantly, caspase-8 modulates expression of Bcl-2 family members and inducible nitric oxide synthase (iNOS) to promote activation of the mitochondrial apoptotic effectors, BAX and BAK.

2021-12-15 | GSE161179 | GEO

Expression data from bone marrow neutrophils with or without LPS stimulation in wild type and miR-125a deficient mice

Project description:Neutrophil activation plays a critical role in the inflammatory response to gram-negative bacterial infections. Lipopolysaccharide (LPS) from gram-negative bacterial has been shown to be a major mediator of neutrophil activation to produce pro-inflammatory cytokines, chemokines and ROS which are important to tissue damage in LPS induced septic shock. We used microarrays to detail the global gene expression of neutrophils from miR-125a+/+ and miR-125a-/- mice after LPS stimulation.

2014-12-02 | GSE63739 | GEO

Single cell RNA-seq of intestine from E18.5 Mlkl -/- and Casp8 C362A/C362A Mlkl -/- embryos

Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumour necrosis factor receptor 1), and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like). Mice lacking caspase-8 display MLKL-dependent embryonic lethality, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that caspase-8 C362A triggers ASC speck formation and caspase-1-dependent pyroptosis in MLKL-deficient intestinal epithelial cells (IECs) around embryonic day 18. Pyroptosis contributed to the perinatal lethal phenotype because a number of Casp8 C362A/C362A Mlkl-/- Casp1-/- mice survived beyond weaning. Transfection studies suggested inactive caspase-8 adopts a distinct conformation to wild-type caspase-8, enabling it to engage the caspase-1 adaptor ASC. Wild-type caspase-8 was found in the Triton X-100 soluble fraction, whereas wild-type caspase-8 inhibited with the pan-caspase inhibitor emricasan, or inactive caspase-8 mutant C362A, were detected in the insoluble fraction. Moreover, inhibited or inactive caspase-8 shifted ASC into the insoluble fraction. Perinatal lethality was recapitulated when expression of caspase-8 C362A was restricted to IECs, but intriguingly, only in the absence of MLKL. Hence, unanticipated plasticity in death pathways is revealed such that IECs can undergo caspase-1-dependent death when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.

2019-09-20 | GSE132133 | GEO

Aging Induced Syntaxin 4 Deficiency Mediates Brown Adipose Tissue Pyroptosis and Thermogenic Dysfunction

Project description:Aging, chronic high fat diet feeding and housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Syntaxin 4 (STX4) was identified as a healthy longevity gene, in contrast endogenous STX4 protein levels in BAT declined in aged mice resulting in pyroptotic activation of caspase 1/4 signaling pathway. Single nuclei RNA sequencing of aged mice identified a specific brown adipocyte population of UCP1low cells that were Stx4 low and pyroptotic. Similarly, UCP1Stx4KO mice led to age-dependent loss of brown adipose tissue mass concomitant with increased pyroptosis whereas restoring STX4 expression protected against pyroptosis and decline in thermogenic activity. Moreover, STX4 deficiency reduced oxidative phosphorylation, glucose uptake and glycolysis leading to reduced ATP levels, a known signal for pyroptosis. All these data demonstrate a new model of rapid brown adipocyte involution and that physiologic aging and BAT involution results from pyroptotic signaling activation.

2024-02-26 | GSE229999 | GEO

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