Lipin-1 promotes macrophage mitochondrial fission for improved inflammation resolution 2753

Abstract Description Chronic inflammation drives the pathophysiology of many cardiometabolic diseases. Pro-resolving macrophages (Møs) resolve inflammation and restore tissue homeostasis via lipid metabolism-dependent efferocytosis. Understanding the regulatory pathways that control Mø lipid metabolic profiles is essential for uncovering mechanisms of inflammation resolution. We have shown that lipin-1, a phosphohydrolase and a transcriptional co-regulator, promotes inflammation resolution by enhancing β-oxidation and efferocytosis. Our current study aims to define the mechanisms by which Mø lipin-1 promotes β-oxidation, efferocytosis and inflammation resolution. Using myeloid-specific lipin-1 knockout (lipin-1mKO) mice and littermate controls, we show that lipin-1 facilitates mitochondrial fission, producing fragmented mitochondria with enhanced β-oxidation capacity compared to elongated mitochondria. Additionally, lentiviral transduction of lipin-1mKO Møs with specific truncated forms of lipin-1 suggests that a novel non-canonical activity of lipin-1 is sufficient to restore and augment efferocytosis. Our findings uncover a novel role for lipin-1 in coordinating mitochondrial structure and metabolic function in macrophages. This deeper understanding of lipin-1’s influence on mitochondrial dynamics and macrophage function advances our knowledge of the cellular mechanisms underlying inflammation resolution and may inform future investigations into metabolic regulation in immune responses. Funding Sources Supported by NIH under grant number P20GM134974 and R01HL163106; and CCDS under grant number CCDS000013 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)