Arachidonic Acid Metabolism Controls Macrophage Alternative Activation Through Regulating Oxidative Phosphorylation in PPAR Dependent Manner

Macrophage polarization is mainly steered by metabolic reprogramming in the tissue 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 macrophage polarization models, we revealed a pivotal role for arachidonic acid metabolism in determining the phenotype of M2 macrophages. We demonstrated that macrophage M2 polarization was inhibited by arachidonic acid, but inversely facilitated by its derived metabolite prostaglandin E2 (PGE2). Furthermore, PPAR gamma bridges these two seemingly unrelated processes via modulating oxidative phosphorylation (OXPHOS). Through inhibiting PPAR gamma, PGE2 enhanced OXPHOS, resulting in the alternative activation of macrophages, which was counterweighted by the activation of PPAR gamma. This connection between PGE2 biosynthesis and macrophage M2 polarization also existed in human and mouse esophageal squamous cell carcinoma. Our results highlight the critical role of arachidonic acid and metabolic PGE2 as immune regulators in modulating tissue homeostasis and pathological process.