Trained immunity promotes inflammation by dampening efferocytosis 4512

Abstract Description Atherosclerotic cardiovascular disease is the leading global cause of death. Atheromas linked to clinical events are characterized by large necrotic cores, resulting from defective efferocytosis, the clearance of apoptotic cells (ACs). Recently, a phenomenon that facilitates long-lasting innate immune memory called ‘trained immunity’ has been identified. Trained immunity is driven by epigenetic and metabolic rewiring of innate immune cells in response to specific stimuli, such as oxidized low-density lipoproteins (oxLDL). This ‘priming’ results in macrophages (Mφs) that are rewired to mount an augmented inflammatory response. We hypothesize that trained immunity in Mφs promotes inflammation by impairing efferocytosis. Murine bone marrow progenitors treated with oxLDL for 24 hours and differentiated into Mφs (BMDMφs) were able to ingest a first round of ACs better than untrained BMDMφs yet had an impaired ability to take up additional ACs, reflecting a defect in continual efferocytosis. We then transplanted bone marrow from Ldlr-/- mice on chow or Western diets into naïve C57BL/6 recipients. After recovery, elicited peritoneal Mφs from recipients receiving marrow from Western diet fed Ldlr-/- mice not only displayed impaired efferocytosis, but also significantly upregulated PGE2 production. These findings suggest that oxLDL/Western diet training impairs efferocytosis and resolution, with heritable effects. Future work will explore the implications for atheroprogression Funding Sources 5R01HL159487-04 (NIH/NHLBI) 1F31HL172670-01 (NIH/NHLBI) 5T32AI138932-05 (NIH/NIAID) Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)