NLRP3炎性小体异常活化可加剧多种炎症疾病的进程，因此，抑制NLRP3炎性小体活化可改善疾病的进展。VSIG4是特异表达与巨噬细胞表面的B7家族分子，前期研究我们发现VSIG4通过下游的衔接蛋白MS4a6D向巨噬细胞传递信号并促进A20表达，进而负调NLRP3及proIL-1β基因转录从而改善结肠炎、EAE及胰岛素抵抗等多种疾病的进展，但VSIG4/MS4a6D复合体上调A20的机制未知。本研究拟使用RNAi、Co-IP及Western-blot等技术探讨其通过活化Akt/PI3K-ERK-STATs通路促进A20表达的分子机制；利用MS4a6D KO小鼠研究其对多种炎症性疾病进程的影响；最后使用VSIG4激动型抗体于体内探讨增强VSIG4信号对EAE等疾病的干预效果。本研究结果将明确VSIG4抑制NLRP3炎性小体活化的分子机制，为NLRP3介导的多种炎症疾病的临床治疗提供新策略。

The hyperactivation of NLRP3 inflammasome contributes to the pathogenesis of multiple diseases whereas the mechanisms negatively regulating this process are poorly understood. We here illustrated that V-set immunoglobulin domain-containing 4 (VSIG4, also called complement receptor of the immunoglobulin superfamily, CRIg), which expresses specifically in resting macrophages, attenuates NLRP3 inflammasome activation and IL-1β secretion. Macrophages lacking Vsig4 have increased basal and LPS-induced NLRP3 and proIL-1β expression in vitro. In parallel, Vsig4-/- mice are more susceptible to develop experimental autoimmune encephalomyelitis (EAE) as well as suffer from high fat diet (HFD)-caused obesity and insulin tolerance due to overburden of NLRP3 inflammasome- mediated IL-1β in vivo. Moreover, enhancing IL-1β also protected Vsig4-/- mice from dextran sulfate sodium (DSS)-induced colitis. Conversely, deletion of NLRP3, Caspase-1 or IL-1 receptor-1 (IL-1R1) in Vsig4-/- mice, respectively, dramatically reverses these effects. Mechanically, VSIG4 promotes the expression of A20, which inhibits the activation of NF-kB and thus lead to attenuate the gene transcription encoding for NLRP3-inflammasome components, through interacting with MS4A6D, a four-pass membrane protein of the MS4A family. In this project, we would detect and confirm that MS4a6D controls the expression of NLRP3 components by upregulating Akt/PI3K-ERK-STATs cascades- mediated A20 expression. Furthermore, MS4A6D-/- animals would be used to analyze whether they phenocopy Vsig4-/- mice and deteriorate the development of several kinds of inflammatory diseases including EAE, DSS-caused colitis et al. Finally, WT mice would be injected with VSIG4 agonist mAbs to confirm that this administration would be suitable for disease therapy. These results reveal that VSIG4 attenuates NLRP3 inflammasome activation and manipulation of VSIG4/MS4A6D signaling would be usefully for inflammatory disease therapy.