Arachidonic acid metabolism controls macrophage alternative activation through regulating oxidative phosphorylation in PPARG dependent manner

Macrophages polarization is mainly controlled by metabolic reprogramming in microenvironment, thus leading to distinct outcomes of various diseases. However, the role of lipid metabolism in the regulation of macrophage alternative activation is incompletely understood. Using human THP-1 and mouse bone marrow derived macrophages polarization models, we revealed a pivotal role for arachidonic acid metabolism in controlling the polarization of M1 and M2 macrophages. We demonstrated that M2 macrophage polarization was inhibited by arachidonic acid, but inversely facilitated by its derived metabolite prostaglandin E2 (PGE2). Furthermore, PPARG bridges these two unconnected processes via modulating oxidative phosphorylation. These results highlight the critical role of arachidonic acid metabolism as an immune regulator in modulating metabolic homeostasis and pathological process.