PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [RNA-seq]

Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.