Lipin-1 promotes mitochondrial respiration to facilitate macrophage pro-resolving responses 2253765

Abstract

Abstract Introduction Atherosclerotic cardiovascular disease, a chronic inflammatory disorder, remains the leading cause of death globally. Macrophages (Møs) promote inflammation resolution and atherosclerosis regression by eating up apoptotic cells via efferocytosis. This imposes a metabolic burden on Møs that requires the efficient catabolism of lipids derived from efferocytic cargoes for effective pro-resolving responses and plaque stability. Our data suggest that lipin-1 attenuates atherosclerosis and promotes inflammation resolution by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and efferocytosis. However, the mechanism by which lipin-1 aids OXPHOS and efferocytosis in pro-resolving macrophages is unknown. Therefore, we hypothesize that lipin-1 drives these processes by facilitating cardiolipin synthesis. Methods We used flow cytometry, fluorescence microscopy, mass spectrometry and RNA interference to assess cardiolipin levels and their impact on efferocytosis in lipin-1 knockout (lipin-1 KO) and wildtype (WT) bone marrow-derived Møs. Also, mitochondrial-ER contact sites (MERCs) formation in WT and lipin-1 KO Mø was observed by electron microscopy. Results Lipin-1 KO Møs had a significant reduction in cardiolipin, a mitochondria-exclusive phospholipid critical for mitochondrial structure and OXPHOS. Reducing cardiolipin synthesis in WT Møs significantly impaired their efferocytic capacity. Also, in response to IL-4, lipin-1 KO Møs exhibited significantly fewer MERCs. MERCs regulate the transfer of lipid precursors essential for cardiolipin synthesis in the mitochondria. Conclusion Our findings show that lipin-1 aids MERCs formation and cardiolipin synthesis to support macrophage efferocytosis and pro-resolving responses. This deepens our insight into the cellular and molecular mechanisms driving inflammation resolution and atherosclerosis regression, which may inform future studies on metabolic regulation of immune responses in chronic inflammation. Funding Source 1. NIH under grant number P20GM134974 and R01HL163106, 2. CCDS under grant number CCDS000013, 3. AHA predoctoral fellowship under grant number 25PRE1373728 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)