Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1147583 | ENA |
REPOSITORIES: ENA
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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
Project description:Neutrophils play a pivotal role in innate immunity and participate in a range of immunological disorders. Excessive neutrophil extracellular traps formed at infection and tissue damage sites are detrimental to the local tissue and further exacerbate inflammation. Protein arginine deiminases mediate histone citrullination and NET formation thereby regulating endotoxin shock response. However, the molecular mechanisms are less known. Here we report that inhibition of netosis attenuates inflammation in a LPS induced lethal endotoxic shock model in mice. Albeit a higher number of neutrophils are accumulated in peritoneal cavity the primary inflammatory site, the level of inflammatory signals is greatly reduced after netosis inhibition with a PAD inhibitor. In lungs under endotoxic stress, gene expression analyses indicate that LPS induced a drastic increase in inflammatory gene expression. In contrast, lung tissue damage and inflammation were much reduced after PAD inhibition to reduce netosis. In summary, we found NET formation inhibition as a new avenue to manage inflammatory damages under endotoxic stress.
2022-12-01 | GSE203340 | GEO
Project description:We aimed to understand the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of lipopolysaccharide (LPS)-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, on liver RNA sequencing (RNAseq) data, Ingenuity® Pathway Analysis (IPA ®) was used to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2715 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptors (TNFRs) mediated processes in wild-type mice. The disruption of CypD reduced the LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.
2019-03-07 | GSE79059 | GEO
Project description:Mitochondrial electron transport chain (ETC) function modulates macrophage biology, however, mechanisms underlying mitochondrial ETC control of macrophage immune responses are not fully understood. Here we report that mutant mice with mitochondrial ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondrial CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Surprisingly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondrial CIII-deficient BMDMs following LPS stimulation. Additionally, mitochondrial CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondrial CIII generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation
2024-12-19 | GSE282257 | GEO
Project description:Role of sulfiredoxin in the tolerance to lipopolysaccharide-induced endotoxic shock
2011-01-01 | E-MEXP-2856 | biostudies-arrayexpress
Project description:Purpose: Characterize the gene expression profile of of peritoneal mouse macrophages in Endotoxic shock and Tolerance through RNA sequencing Methods: RNA sequencing of RNA from peritoneal macrophages in Endotoxic shock and Tolerance isolated by peritoneal lavage and FACS sorting (F4/80+ CD11b+) Results: Endotoxic shock and Tolerance peritoneal mouse macrophages display differential gene expression. Conclusions: Endotoxic shock and Tolerance peritoneal mouse macrophages display differential gene expression.
2023-09-13 | GSE207328 | GEO
Project description: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.
2018-08-07 | GSE115094 | GEO
Project description:Gasdermin D (GSDMD) is the executioner of pyroptosis, which is important for host defense against pathogen infection. After activation, caspase-mediated cleavage of GSDMD liberates an N-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and subsequent release of proinflammatory cytokines. How this process is spatiotemporally controlled to promote pyroptosis in cells has been a fundamental, unaddressed question. Here, we identify GSDMD as a substrate for reversible S-palmitoylation on cysteine 192 (Cys192) in response to lipopolysaccharide (LPS) stimulation. We found that the palmitoyl acyltransferase DHHC7palmitoylates GSDMD to direct its cleavage by caspases in pyroptosis by promoting the interaction of GSDMD and caspases. We further show that after GSDMD cleavage, palmitoylation of GSDMD-NTpromotes its plasma membrane translocation and binding, and then acyl protein thioesterase 2 (APT2) depalmitoylates GSDMD-NT to unmask the Cys192 residue to promote oxidation-mediated oligomerization and pyroptosis. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, extends the survival of mice from LPS-induced lethal septic shock and sensitizes mice to bacterial infection. Thus. our findings reveal a model through which a palmitoylation-depalmitoylationrelay spatially and temporally controls GSDMD activation in pyroptosis.
2024-02-25 | GSE252911 | GEO
Project description:Gasdermin D (GSDMD) is the executioner of pyroptosis, which is important for host defense against pathogen infection. After activation, caspase-mediated cleavage of GSDMD liberates an N-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and subsequent release of proinflammatory cytokines. How this process is spatiotemporally controlled to promote pyroptosis in cells has been a fundamental, unaddressed question. Here, we identify GSDMD as a substrate for reversible S-palmitoylation on cysteine 192 (Cys192) in response to lipopolysaccharide (LPS) stimulation. We found that the palmitoyl acyltransferase DHHC7palmitoylates GSDMD to direct its cleavage by caspases in pyroptosis by promoting the interaction of GSDMD and caspases. We further show that after GSDMD cleavage, palmitoylation of GSDMD-NTpromotes its plasma membrane translocation and binding, and then acyl protein thioesterase 2 (APT2) depalmitoylates GSDMD-NT to unmask the Cys192 residue to promote oxidation-mediated oligomerization and pyroptosis. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, extends the survival of mice from LPS-induced lethal septic shock and sensitizes mice to bacterial infection. Thus. our findings reveal a model through which a palmitoylation-depalmitoylationrelay spatially and temporally controls GSDMD activation in pyroptosis.
2024-02-25 | GSE252893 | GEO
Project description:Ca2+ signaling cascades are essential for various immune cell functions. As such, most cells have negative regulators of Ca2+ homeostasis that strictly regulate cytosolic Ca2+ concentration, such as Ca2+-activated monovalent cation channels (CAMs). Transient receptor potential melastatin-related 5 channel (TRPM5), a CAM, is expressed in B lymphocytes. However, its functional role in the immune system is poorly understood. Here, we show that TRPM5 negatively modulates Ca2+ influx, thereby regulating lipopolysaccharide (LPS)-induced proliferative and inflammatory responses by B cells. Trpm5-deficient mice exhibited increased Ca2+ influx, enhanced proliferative responses, and increased production of inflammatory cytokines interleukin-6 and CXCL10 in LPS-stimulated B cells. However, Ca2+ chelation reduced LPS-induced cytokine production by Trpm5-deficient B cells. Furthermore, Trpm5-deficient mice showed exacerbation of endotoxic shock with high mortality. Our findings demonstrate the importance of TRPM5-dependent regulatory mechanisms in LPS-induced Ca2+ signaling of splenic B cells.
2020-06-01 | GSE134443 | GEO