Porcine GWAS identifies ACOT11 as regulator for macrophage IL-1β maturation via IFNGR2 palmitoylation.

Fatty acid metabolism mediates macrophage function; however, the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin (IL)-1β production 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-1β maturation 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)-γ receptor (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.