VSIG4 Attenuates NLRP3 and Ameliorates Neuroinflammation via JAK2-STAT3-A20 Pathway after Intracerebral Hemorrhage in Mice

Ji, Na; Wu, Lirong; Shi, Hui; Li, Qianlu; Yu, Anyong; Yang, Zhao

doi:10.1007/s12640-021-00456-5

Cited by 12 publications

(6 citation statements)

References 35 publications

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“…It negatively regulates inflammatory processes by suppressing T cell function and activating macrophage immunity by binding to C3b/iC3b and mediates transcriptional repression of NLRP3 and Il-1β in macrophages [26]. VSIG4 also attenuates NLRP3 via the JAK2-STAT3-A20 pathway and ameliorates neuroinflammation after brain hemorrhage in mice [13]. Several studies have reported that VSIG4 expression improves liver fibrosis in hepatic Kupffer cells [27,28].…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction

Wang¹,

Li²,

Li³

et al. 2023

Theranostics

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M2 macrophage-mediated tissue repair plays an important role in acute myocardial infarction (AMI). Additionally, VSIG4, which is mainly expressed on tissue-resident and M2 macrophages, is crucial for the regulation of immune homeostasis; however, its effects on AMI remain unknown. In this study, we aimed to investigate the functional significance of VSIG4 in AMI using VSIG4 knockout and adoptive bone marrow transfer chimeric models. We also determined the function of cardiac fibroblasts (CFs) through gain-or loss-of-function experiments. We showed that VSIG4 promotes scar formation and orchestrates the myocardial inflammatory response after AMI, while also promoting TGF-β1 and IL-10. Moreover, we revealed that hypoxia promotes VSIG4 expression in cultured bone marrow M2 macrophages, ultimately leading to the conversion of CFs to myofibroblasts. Our results reveal a crucial role for VSIG4 in the process of AMI in mice and provide a potential immunomodulatory therapeutic avenue for fibrosis repair after AMI.

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Section: Discussionmentioning

confidence: 99%

“…VSIG4 -/- (gene symbol: CRIg; VSIG4KO) mice with a C57BL/6 background were generated as previously described 13 . Wild-type (WT) C57BL6/J mice (20-25 g, male, 6-16 weeks old; Laboratory Animal of Zunyi Medical University, Zunyi, China) were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction

Wang¹,

Li²,

Li³

et al. 2023

Theranostics

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“…Zhu H reported that STAT3 activation can promote the occurrence and development of inflammation, leading to increased cerebral edema after ICH and damage to neurons around the hematoma, and NLRP3 is a downstream molecule of STAT ( Lee et al, 2006 ). In addition, the findings from mouse experiments suggest that NLRP3 is the key to the aggravation of ICH injury caused by STAT3 ( Ji et al, 2022 ). Our results showed that NLRP3 was significantly upregulated in the brain tissues of ICH patients, and the AUC of NLRP3 was greater than 0.89, which indicates that NLRP3 is a key gene for ICH and has strong predictive value for ICH.…”

Section: Discussionmentioning

confidence: 99%

The use of multiple datasets to identify autophagy-related molecular mechanisms in intracerebral hemorrhage

et al. 2023

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Background: Intracerebral hemorrhage (ICH) is a stroke syndrome with high mortality and disability rates, but autophagy’s mechanism in ICH is still unclear. We identified key autophagy genes in ICH by bioinformatics methods and explored their mechanisms.Methods: We downloaded ICH patient chip data from the Gene Expression Omnibus (GEO) database. Based on the GENE database, differentially expressed genes (DEGs) for autophagy were identified. We identified key genes through protein–protein interaction (PPI) network analysis and analyzed their associated pathways in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene-motif rankings, miRWalk and ENCORI databases were used to analyze the key gene transcription factor (TF) regulatory network and ceRNA network. Finally, relevant target pathways were obtained by gene set enrichment analysis (GSEA).Results: Eleven autophagy-related DEGs in ICH were obtained, and IL-1B, STAT3, NLRP3 and NOD2 were identified as key genes with clinical predictive value by PPI and receiver operating characteristic (ROC) curve analysis. The candidate gene expression level was significantly correlated with the immune infiltration level, and most of the key genes were positively correlated with the immune cell infiltration level. The key genes are mainly related to cytokine and receptor interactions, immune responses and other pathways. The ceRNA network predicted 8,654 interaction pairs (24 miRNAs and 2,952 lncRNAs).Conclusion: We used multiple bioinformatics datasets to identify IL-1B, STAT3, NLRP3 and NOD2 as key genes that contribute to the development of ICH.

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“…found that macrophages lacking VSIG4 showed increased activation of the NLRP3 inflammasome upon stimulation ( 89 ). VSIG4 was found to interact with the transmembrane protein MS4A6D to form a surface inhibitory signaling complex, leading to attenuated NLRP3 inflammasome activation via a JAK2-STAT3-A20 signaling cascade ( 89 , 90 ). In addition, VSIG4 was also able to intervene in mitochondrial pyruvate metabolism in macrophages by activating the PI3K-Akt-STAT3 pathway, thereby resulting in reduced oxidative phosphorylation and diminished M1 polarization of macrophages ( 91 ).…”

Section: Vsig4mentioning

confidence: 99%

V-Set and immunoglobulin domain containing (VSIG) proteins as emerging immune checkpoint targets for cancer immunotherapy

et al. 2022

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The development of immune checkpoint inhibitors is becoming a promising approach to fight cancers. Antibodies targeting immune checkpoint proteins such as CTLA-4 and PD-1 can reinvigorate endogenous antitumor T-cell responses and bring durable advantages to several malignancies. However, only a small subset of patients benefit from these checkpoint inhibitors. Identification of new immune checkpoints with the aim of combination blockade of multiple immune inhibitory pathways is becoming necessary to improve efficiency. Recently, several B7 family-related proteins, TIGIT, VSIG4, and VSIG3, which belong to the VSIG family, have attracted substantial attention as coinhibitory receptors during T-cell activation. By interacting with their corresponding ligands, these VSIG proteins inhibit T-cell responses and maintain an immune suppressive microenvironment in tumors. These results indicated that VSIG family members are becoming putative immune checkpoints in cancer immunotherapy. In this review, we summarized the function of each VSIG protein in regulating immune responses and in tumor progression, thus providing an overview of our current understanding of VSIG family members.

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VSIG4 Attenuates NLRP3 and Ameliorates Neuroinflammation via JAK2-STAT3-A20 Pathway after Intracerebral Hemorrhage in Mice

Cited by 12 publications

References 35 publications

Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction

Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction

The use of multiple datasets to identify autophagy-related molecular mechanisms in intracerebral hemorrhage

V-Set and immunoglobulin domain containing (VSIG) proteins as emerging immune checkpoint targets for cancer immunotherapy

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