Abstract Thu117: EDIL3 Deficiency Exacerbates Atherosclerosis by Impairing Macrophage Efferocytosis

Introduction: EDIL3 has been identified as an endogenous inhibitor of neutrophil adhesion, playing a critical role in the regulation of inflammation. Despite its known functions, its potential involvement in the pathogenesis of atherosclerosis remains largely unexplored. This study aims to investigate the relationship between EDIL3 and atherosclerosis, with the goal of uncovering new insights that could enhance our understanding and inform the treatment of atherosclerotic diseases. Methods: We crossbred Edil3 -/- mice with Apoe -/- mice to generate Apoe/Edil3 -/- mice. To induce atherosclerosis, we utilized Edil3 knockout combined with a high-fat diet (HFD). We then compared the progression of atherosclerosis between Apoe/Edil3 -/- mice and Apoe -/- mice to investigate the role of EDIL3 in the disease. The severity of atherosclerotic changes, neutrophil infiltration, and efferocytosis were assessed using oil red O staining and immunofluorescence staining. Additionally, RNA sequencing was performed to elucidate the downstream mechanisms through which Edil3 influences the pathogenesis of atherosclerosis. Results: We observed that, compared to Apoe -/- mice, the aorta of Apoe/Edil3 -/- mice displayed a greater number of atherosclerotic plaques, with lesions more widely distributed at both 10 weeks (0.12 vs. 0.33, P = 0.0105) and 22 weeks (0.28 vs. 0.51, P = 0.0122) following the initiation of HFD. Additionally, Apoe/Edil3 -/- mice developed more severe necrotic cores within the lesions, as well as a higher ratio of necrotic area to total lesion area after 10 weeks (44,003 µm 2 vs. 12,055 µm 2 , P < 0.0001; 11.31% vs. 5.02%, P = 0.0011) and 22 weeks (117,644 µm 2 vs. 31,542 µm 2 , P = 0.0013; 13.10% vs. 5.95%, P = 0.0220) of HFD. Further analysis revealed that the ratio of free apoptotic cells to apoptotic cells engulfed by lesional macrophages was significantly higher in Apoe/Edil3 -/- mice (2.375 vs. 0.3575, P = 0.0040). Moreover, RNA sequencing demonstrated that genes associated with efferocytosis, including Pparg , Cd36 , and Abca1 , were downregulated in Apoe/Edil3 -/- mice compared to Apoe -/- mice. Conclusion: EDIL3 may exert a protective role in the pathological mechanism of atherosclerosis by promoting the efferocytosis of macrophages within atherosclerotic plaques.