免疫代谢学研究发现许多核心代谢调节分子同样参与免疫细胞的功能调控并影响相关炎症代谢性疾病的发生。NLRP3炎症小体可被相关代谢压力激活进而在慢性炎症及相关代谢紊乱中发挥重要作用。SCAP/SREBP2/Insig-1通过感受胞内胆固醇含量以控制胆固醇的“从头合成”，是机体维持胆固醇平衡的关键机制。SCAP/SREBP2/Insig-1是否直接参与NLRP3炎症小体的活化将成为研究代谢-免疫稳态互调机制的重要突破口。我们前期研究发现SCAP/SREBP2参与NLRP3炎症小体的激活，其特异性抑制剂或表达缺失后均显著抑制NLRP3炎症小体的活化。作用机制可能通过与NLRP3结合进而促进其胞内转位及ASC speck的形成来实现。本课题将进一步明确NLRP3炎症小体活化时SCAP/SREBP2的活性变化及其对NLRP3炎症小体的调控，为解析代谢紊乱疾病中相关炎症积累提供新的理论依据和分子靶点。

Metabolism and immunity, have evolved to share a common modular architecture that allows extensive bidirectional communication and coordination. Indeed, recent immunometabolism observations have highlighted numerous functionally critical metabolic regulatory modules located within diverse immune circuits，which is critical for the pathogenesis of inflammatory metabolic disorders. NLRP3 inflammasome is implicated in recognizing certain "metabolic stress" signals leading to the chronic inflammation involved in diverse metabolic disorders. Cholesterol sensing complex SCAP/SREBP2/Insig-1 plays key role in the cholesterol homeostatic regulation by controlling the "de novo cholesterol biosynthesis". Whether SCAP/SREBP2/Insig-1 complex directly regulates NLRP3 inflammasome activation is important for elucidating the crosstalk between metabolism and immunity. We show that SCAP/SREBP2 could promote the activation of NLRP3 inflammasome evidenced by the suppressed NLRP3 inflammasome activation by specific inhibitors or deficiency of SCAP/SREBP2. We further found that SCAP/SREBP2 might promote NLRP3 inflammasome activation via facilitating the translocation of NLRP3 and ASC speck formation. This proposal will focus on the further study of the regulation of NLRP3 inflammasome by SCAP/SREBP2 and the underlying mechanism. Collectively, we expect to identify a novel regulatory mechanism of NLRP3 inflammasome by metabolic cues which might be targeted for the treatment of inflammatory metabolic disorders.