Macrophage-specific deletion of MIC26 (APOO) mitigates advanced atherosclerosis by increasing efferocytosis

传出细胞增多 炎症 巨噬细胞 细胞凋亡 M2巨噬细胞 吞噬作用 基因剔除小鼠 免疫学 载脂蛋白E 梅尔特克 医学 细胞生物学 内科学 生物 生物化学 信号转导 疾病 体外 受体 受体酪氨酸激酶
作者
Xiaoyu Tang,Zhijie Huang,Wei Wang,Jin Chen,Donglu Qin,Daoquan Peng,Bilian Yu
出处
期刊:Atherosclerosis [Elsevier BV]
卷期号:386: 117374-117374 被引量:3
标识
DOI:10.1016/j.atherosclerosis.2023.117374
摘要

Background and aims Recent studies have suggested that MIC26 (apolipoprotein O, APOO), a novel mitochondrial inner membrane protein, is involved in inflammation. Thus, the role of macrophage MIC26 in acute inflammation and chronic inflammatory disease atherosclerosis was investigated. Methods Macrophage-specific MIC26 knockout mice (MIC26LysM) were generated by crossing Apooflox/flox and LysMcre+/- mice. An endotoxemia mouse model was generated to explore the effects of macrophage MIC26 deficiency on acute inflammation, while an atherosclerosis mouse model was constructed by crossing MIC26LysM mice with Apoe−/− mice and challenged with a Western diet. Atherosclerotic plaques, primary macrophage function, and mitochondrial structure and function were analyzed. Results MIC26 knockout did not affect the median survival time and post-injection serum interleukin 1β concentrations in mice with endotoxemia. Mice with MIC26 deficiency in an Apoe−/− background had smaller atherosclerotic lesions and necrotic core than the control group. In vitro studies found that the loss of MIC26 did not affect macrophage polarization, apoptosis, or lipid handling capacity, but increased efferocytosis (the ability to clear apoptotic cells). An in situ efferocytosis assay of plaques also showed that the ratio of macrophage-associated apoptotic cells to free apoptotic cells was higher in the MIC26-deficient group than in the control group, indicating increased efferocytosis. In addition, an in vivo thymus efferocytosis assay indicated that MIC26 deletion promoted efferocytosis. Mechanistically, the loss of MIC26 resulted in an abnormal mitochondrial inner membrane structure, increased mitochondrial fission, and decreased mitochondrial membrane potential. Loss of MIC26 reduced mitochondria optic atrophy type 1 (OPA1) protein, and OPA1 silencing in macrophages promoted efferocytosis. Overexpression of OPA1 abolished the increase in efferocytosis produced by MIC26 deficiency. Conclusions Macrophage MIC26 deletion alleviated advanced atherosclerosis and necrotic core expansion by promoting efferocytosis. This mechanism may be related to the increased mitochondrial fission caused by reduced mitochondrial OPA1.
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