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Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages.

ABSTRACT: Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro-inflammatory cytokines. In humans, it depends on caspase 1/4-activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1-F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1-F2-deficient mutant of a contemporary IAV resulted in higher levels of caspase-1 activation, cleavage of gasdermin D, and release of LDH and IL-1β. Mechanistically, PB1-F2 limits transition of NLRP3 from its auto-repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly.

SUBMITTER: Boal-Carvalho I

PROVIDER: S-EPMC7726813 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages

Project description:Pyroptosis is a fulminant form of macrophage cell death, contributing to release of proinflammatory cytokines. In humans it depends on caspase 1/4-activation of gasdermin D and is characterized by release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1-F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1-F2-deficient mutant of a contemporary IAV resulted in higher levels of caspase-1 activation, cleavage of gasdermin D as well as release of LDH and IL-1?. Mechanistically, PB1-F2 limits transition of NLRP3 from its autorepressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly.

| S-SCDT-EMBOR-2020-50421V1 | biostudies-other

MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation.

Project description:The NLRP3 inflammasome plays a key role in responding to pathogens, and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1β and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1β and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1β production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.

| S-EPMC10548170 | biostudies-literature

MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation

Project description:The NLRP3 inflammasome plays a key role in responding to pathogens and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1 and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1β and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1β production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.

| S-SCDT-10_15252-EMBJ_2023113481 | biostudies-other

NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling.

Project description:Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK7 mRNA and protein expression and pyroptosis-associated factors, including Caspase-1 (p45, p20), NLRP3, and GSDMD, were upregulated in IBD tissues. NEK7 knockdown abolish ATP + LPS-induced pyroptosis in vitro and improved DSS-induced chronic colitis in vivo. NEK7 interacted with NLRP3, as revealed by Co-IP and GST pull-down assays, to exert its effects. Moreover, short-term LPS treatment alone induced no significant changes in NEK7 protein level. TLR4/NF-κB signaling in MODE-K cells could be activated by LPS treatment. LPS-induced NEK7 upregulation could be significantly reversed by JSH-23, an inhibitor of p65. Furthermore, LUC and ChIP assays revealed that RELA might activate the transcription of NEK7 via targeting its promoter region. LPS-induced TLR4/NF-κB activation causes an increase in NEK7 expression by RELA binding NEK7 promoter region. In conclusion, NEK7 interacts with NLRP3 to modulate NLRP3 inflammasome activation, therefore modulating the pyroptosis in MODE-K cells and DSS-induced chronic colitis in mice. We provide a novel mechanism of NEK7-NLRP3 interaction affecting IBD via pyroptosis.

| S-EPMC6885517 | biostudies-literature

NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages.

Project description:A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20?Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1? as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5?Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation.

| S-EPMC5386456 | biostudies-other

cFLIPL protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation.

Project description:Cell death and inflammation are interdependent host responses to infection. During pyroptotic cell death, interleukin-1? (IL-1?) release occurs through caspase-1 and caspase-11-mediated gasdermin D pore formation. In vivo, responses to lipopolysaccharide (LPS) result in IL-1? secretion. In vitro, however, murine macrophages require a second "danger signal" for the inflammasome-driven maturation of IL-1?. Recent reports have shown caspase-8-mediated pyroptosis in LPS-activated macrophages but have provided conflicting evidence regarding the release of IL-1? under these conditions. Here, to further characterize the mechanism of LPS-induced secretion in vitro, we reveal an important role for cellular FLICE-like inhibitory protein (cFLIP) in the regulation of the inflammatory response. Specifically, we show that deficiency of the long isoform cFLIPL promotes complex II formation, driving pyroptosis, and the secretion of IL-1? in response to LPS alone.

| S-EPMC7375259 | biostudies-literature

HECTD3 inhibits NLRP3 inflammasome assembly and activation by blocking NLRP3-NEK7 interaction.

Project description:The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1β, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.

| S-EPMC10808187 | biostudies-literature

Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7-NLRP3 interaction.

Project description:The activation of the nucleotide oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is related to the pathogenesis of a wide range of inflammatory diseases, but drugs targeting the NLRP3 inflammasome are still scarce. In the present study, we demonstrated that Licochalcone B (LicoB), a main component of the traditional medicinal herb licorice, is a specific inhibitor of the NLRP3 inflammasome. LicoB inhibits the activation of the NLRP3 inflammasome in macrophages but has no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, LicoB directly binds to NEK7 and inhibits the interaction between NLRP3 and NEK7, thus suppressing NLRP3 inflammasome activation. Furthermore, LicoB exhibits protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including lipopolysaccharide (LPS)-induced septic shock, MSU-induced peritonitis and non-alcoholic steatohepatitis (NASH). Our findings indicate that LicoB is a specific NLRP3 inhibitor and a promising candidate for treating NLRP3 inflammasome-related diseases.

| S-EPMC8811655 | biostudies-literature

S100A8-Mediated NLRP3 Inflammasome-Dependent Pyroptosis in Macrophages Facilitates Liver Fibrosis Progression.

Project description:NLRP3 inflammasome-dependent pyroptosis has been implicated in liver fibrosis progression. However, the definite intrahepatic cell types that undergo pyroptosis and the underlying mechanism as well as the clinical importance remain unclear. Here, augmented levels of pyroptosis-related indicators GSDMD, IL-1β, and IL-18 were verified in both liver fibrosis patients and CCl4-induced fibrotic mouse model. Confocal imaging of NLRP3 with albumin, F4/80 or α-SMA revealed that enhanced NLRP3 was mainly localized to kupffer cells (KCs), indicating that KCs are major cell types that undergo pyroptosis. Targeting pyroptosis by inhibitor MCC950 attenuated the severity and ameliorated liver function in fibrosis models. In addition, elevated S100A8 in liver fibrosis patients was correlated with pyroptosis-related indicators. S100A8 stimulated pyroptotic death of macrophages, which resulted in activation of human hepatic stellate cell line LX-2 cells and increased collagen deposition. Mechanistically, S100A8 activated TLR4/NF-κB signaling and upregulated its target genes NLRP3, pro-IL-1β, and pro-IL-18 expression, and induced reactive oxygen (ROS) abundance to activate NLRP3 inflammasome, finally leading to pyroptotic cell death in macrophages. More importantly, circulating GSDMD had the optimal predicting value for liver fibrosis progression. In conclusion, S100A8-mediated NLRP3 inflammasome-dependent pyroptosis by TLR4/NF-κB activation and ROS production in macrophages facilitates liver fibrosis progression. The identified GSDMD has the potential to be a biomarker for liver fibrosis evaluation.

| S-EPMC9688473 | biostudies-literature

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells.

Project description:Foam cells are specialized lipid-loaded macrophages derived from monocytes and are a key pathological feature of atherosclerotic lesions. Lysophosphatidylcholine (LPC) is a major lipid component of the plasma membrane with a broad spectrum of proinflammatory activities and plays a key role in atherosclerosis. However, the role of LPC in lipid droplet (LD) biogenesis and the modulation of inflammasome activation is still poorly understood. In the present study, we investigated whether LPC can induce foam cell formation through an analysis of LD biogenesis and determined whether the cell signaling involved in this process is mediated by the inflammasome activation pathway in human endothelial cells and monocytes. Our results showed that LPC induced foam cell formation in both types of cells by increasing LD biogenesis via a NLRP3 inflammasome-dependent pathway. Furthermore, LPC induced pyroptosis in both cells and the activation of the inflammasome with IL-1β secretion, which was dependent on potassium efflux and lysosomal damage in human monocytes. The present study described the IL-1β secretion and foam cell formation triggered by LPC via an inflammasome-mediated pathway in human monocytes and endothelial cells. Our results will help improve our understanding of the relationships among LPC, LD biogenesis, and NLRP3 inflammasome activation in the pathogenesis of atherosclerosis.

| S-EPMC6962110 | biostudies-literature

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