Macrophage-associated lipin-1 regulates lipid catabolism to promote effective efferocytosis

Abstract

Abstract Failure to resolve inflammation leads to numerous chronic diseases. Disease resolution requires the effective removal of dead cells by macrophage-mediated efferocytosis. Excess lipid accumulation within macrophages can lead to dysfunction that promotes disease pathogenesis. Efferocytosis results in a significant accumulation of lipid inside the macrophage, yet macrophage continue to function. This suggest that during efferocytosis, macrophages have pathways to ameliorate the high lipid load. We have identified that lipin-1, a regulator of lipid metabolism, is critical to proper macrophage responses during efferocytosis. Lipin-1 is a phosphatidic acid phosphatase that also functions as a transcriptional coregulator. We used mice that lack either lipin-1 enzymatic activity or both functions in myeloid cells to define how lipin-1 regulates excess lipids during efferocytosis. We have demonstrated that mice lacking myeloid-associated lipin-1 have diminished apoptotic cell (AC) clearance in a zymozan model of efferocytosis. Clearance of lipids during efferocytosis is accomplished through beta-oxidation. Bone marrow derived macrophages lacking lipin-1 have reduced oxidative respiration in response to both AC and purified palmitate (lipid), indicating defective lipid catabolism. These data suggest that lipin-1 regulates mitochondrial lipid catabolism to reduce lipid burden during efferocytosis. These studies highlight regulation of lipid metabolic pathways in macrophages during efferocytosis that allow them to handle excess lipid burden and promote disease resolution.