Cholesterol Sensor SCAP-SREBP2 Complex Correlates NLRP3 Inflammasome Activation In Macrophages

Inflammasomes are large complexes that can recognize pathogen associated molecular patterns(PAMPs)and damage associated molecular patterns(DAMPs).Their activation orchestrates important roles in innate immune responses.Cholesterol metabolism is involved in multiple biological process,including immune functions.However,the role of cholesterol metabolism in inflammasome activation remains poorly investigated.Here we have shown that cholesterol homeostatic regulator SCAP-SREBP2 complex takes part in the activation of NLRP3 inflammasome in macrophages.We found that NLRP3 inflammasome activation coupled SREBP2 maturation.Besides,the SCAP-SREBP2 complex and its ER-to-Golgi translocation was required for optimal NLRP3 inflammasome activation.More specifically,the chaperone protein SCAP was necessary during this process,rather than the transcription of cholesterol biosynthetic genes triggered by mature SREBP2.Mechanistically,NLRP3 associated with SCAP and SREBP2 to form a ternary complex.As a chaperone protein,SCAP escorted SREBP2 and NLRP3 to translocate to Golgi.At the Golgi,SREBP2 was cleaved to release its active form for cholesterol biosynthetic gene transcription,while SCAP further escorted NLRP3 adjacent to mitochondria for further inflammasome assembly.In mice model of LPS-induced peritonitis,inhibition of SCAP-SREBP2 could significantly attenuate NLRP3 inflammasome activation,as indicated by decreased level of serum IL-1β(Interleukin-1 beta)和 IL-18(Interleukin 18).Overall,our study identifies the participation of cholesterol biosynthesis in macrophage inflammasome activation,reveals an unrecognized role of SCAP-SREBP2 in NLRP3 inflammasome activation besides controlling cholesterol synthesis,suggests new insights in immune-metabolism crosstalk,and provides potential therapeutic targets for NLRP3-related immune-metabolism diseases.