PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPAR gamma ligand, in a PPAR gamma-dependent manner. Moreover, PPAR gamma is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPAR gamma dramatically affects the oxidation of glutamine. Both glutamine and PPAR gamma have been implicated in alternative activation (AA) of macrophages, and PPAR gamma was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPAR gamma contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPAR gamma functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPAR gamma expression is itself markedly increased by IL4. This suggests that PPAR gamma functions at the center of a feed-forward loop that is central to AA of macrophages.