Dataset Information

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

ABSTRACT: Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1β secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein-protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.

SUBMITTER: Sim J

PROVIDER: S-EPMC8878774 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

Sim JeongMin J Park JeongMan J Kim Suwan S Hwang Sojung S Sung KyoungSu K Lee Jung-Eun JE Yang SeungHo S Cho Kyunggi K Lee SungHwan S Moon Jong-Seok JS Ahn JuWon J Lim Jaejoon J

International journal of molecular sciences 20220212 4

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by gene ...[more]

PMID: 35216164

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Project description:Salmonella typhimurium (S. typhimurium) infection of macrophage induces NLRC4 inflammasome-mediated production of the pro-inflammatory cytokines IL-1β. Post-translational modifications on NLRC4 are critical for its activation. Sirtuin3 (SIRT3) is the most thoroughly studied mitochondrial nicotinamide adenine dinucleotide (NAD+) -dependent deacetylase. We wondered whether SIRT3 mediated-deacetylation could take part in NLRC4 inflammasome activation. Methods: We initially tested IL-1β production and pyroptosis after cytosolic transfection of flagellin or S. typhimurium infection in wild type and SIRT3-deficient primary peritoneal macrophages via immunoblotting and ELISA assay. These results were confirmed in SIRT3-deficient immortalized bone marrow derived macrophages (iBMDMs) which were generated by CRISPR-Cas9 technology. In addition, in vivo experiments were conducted to confirm the role of SIRT3 in S. typhimurium-induced cytokines production. Then NLRC4 assembly was analyzed by immune-fluorescence assay and ASC oligomerization assay. Immunoblotting, ELISA and flow cytometry were performed to clarify the role of SIRT3 in NLRP3 and AIM2 inflammasomes activation. To further investigate the mechanism of SIRT3 in NLRC4 activation, co-immunoprecipitation (Co-IP), we did immunoblot, cellular fractionation and in-vitro deacetylation assay. Finally, to clarify the acetylation sites of NLRC4, we performed liquid chromatography-mass spectrometry (LC-MS) and immunoblotting analysis. Results: SIRT3 deficiency led to significantly impaired NLRC4 inflammasome activation and pyroptosis both in vitro and in vivo. Furthermore, SIRT3 promotes NLRC4 inflammasome assembly by inducing more ASC speck formation and ASC oligomerization. However, SIRT3 is dispensable for NLRP3 and AIM2 inflammasome activation. Moreover, SIRT3 interacts with and deacetylates NLRC4 to promote its activation. Finally, we proved that deacetylation of NLRC4 at Lys71 or Lys272 could promote its activation. Conclusions: Our study reveals that SIRT3 mediated-deacetylation of NLRC4 is pivotal for NLRC4 activation and the acetylation switch of NLRC4 may aid the clearance of S. typhimurium infection.

Dataset Information

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

Publications

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome.

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