Fatty acid metabolism mediates macrophage function;however,the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin(IL)-1βproduction remains to be uncovered.Here,we used genome-wide as...Fatty acid metabolism mediates macrophage function;however,the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin(IL)-1βproduction remains to be uncovered.Here,we used genome-wide association studies(GWAS)to identify several porcine serum IL-1β-related genes,such as the fatty acid metabolizing enzyme acyl-CoA thioesterase 11(ACOT11).We then demonstrated that inflammatory macrophages have low expression of ACOT11,and ACOT11 overexpression inhibits IL-1βmaturation from inflammatory macrophages.Mechanistically,ACOT11 promotes intracellular fatty acids accumulation,including eicosatetraenoic acid(EA)and stearic acid(SA),which inhibit activation of the Janus kinase(JAK)—signal transducer and activator of transcription(STAT)signaling through palmitoylation of interferon(IFN)-γreceptor(IFNGR)2 at C261site.Furthermore,we also found that EA attenuates lipopolysaccharide(LPS)-induced sepsis in mice.Collectively,our findings reveal a mechanism involving ACOT11-mediated post-translational modification that regulates macrophage function and provide a promising therapeutic target for the treatment of inflammatory diseases associated with macrophages.展开更多
基金supported by the National Natural Science Foundation of China(32225047)Double first-class discipline promotion project(2023B10564001)+2 种基金Open Project Program of Sichuan Provincial Key Laboratory of Animal Disease-resistant Nutrition,Sichuan Agricultural University(SZ202301-02)Guangdong Basic and Applied Basic Research Foundation(2022A1515111229)Hainan Provincial Natural Science Foundation of China(325QN483).
文摘Fatty acid metabolism mediates macrophage function;however,the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin(IL)-1βproduction remains to be uncovered.Here,we used genome-wide association studies(GWAS)to identify several porcine serum IL-1β-related genes,such as the fatty acid metabolizing enzyme acyl-CoA thioesterase 11(ACOT11).We then demonstrated that inflammatory macrophages have low expression of ACOT11,and ACOT11 overexpression inhibits IL-1βmaturation from inflammatory macrophages.Mechanistically,ACOT11 promotes intracellular fatty acids accumulation,including eicosatetraenoic acid(EA)and stearic acid(SA),which inhibit activation of the Janus kinase(JAK)—signal transducer and activator of transcription(STAT)signaling through palmitoylation of interferon(IFN)-γreceptor(IFNGR)2 at C261site.Furthermore,we also found that EA attenuates lipopolysaccharide(LPS)-induced sepsis in mice.Collectively,our findings reveal a mechanism involving ACOT11-mediated post-translational modification that regulates macrophage function and provide a promising therapeutic target for the treatment of inflammatory diseases associated with macrophages.
