Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.

Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function and polarization, which is crucial to the resolution of inflammation. The contribution of lipid synthesis to proinflammatory macrophage responses is well understood. However, how lipid synthesis regulates proresolving macrophage responses needs to be better understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that regulates lipid metabolism. We previously demonstrated that lipin-1 supports proresolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage proresolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis, the transport of citrate from the mitochondria, reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO mice and macrophages. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting proresolving macrophage function in response to proresolving stimuli.