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

Xiaoyu Tang; Zhijie Huang; Fengjiao Wang; Jin Chen; Donglu Qin; Daoquan Peng; Bilian Yu

doi:10.1016/j.atherosclerosis.2023.117374

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

Atherosclerosis. 2023 Dec:386:117374. doi: 10.1016/j.atherosclerosis.2023.117374. Epub 2023 Nov 10.

Authors

Xiaoyu Tang¹, Zhijie Huang², Fengjiao Wang², Jin Chen², Donglu Qin², Daoquan Peng³, Bilian Yu⁴

Affiliations

¹ Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Medical Research Center for Systemic Autoimmune Diseases in Hunan Province, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
² Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
³ Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China. Electronic address: pengdq@csu.edu.cn.
⁴ Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Hunan Key Laboratory of Cardiometabolic Medicine, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China. Electronic address: yubilian@csu.edu.cn.

PMID: 37995600
DOI: 10.1016/j.atherosclerosis.2023.117374

Abstract

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 (MIC26^LysM) were generated by crossing Apoo^flox/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 MIC26^LysM 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.

Keywords: Atherosclerosis; Efferocytosis; Macrophage; Mitochondrion.

MeSH terms

Animals
Apolipoproteins E
Apoptosis
Atherosclerosis* / genetics
Atherosclerosis* / metabolism
Endotoxemia / metabolism
Inflammation / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Necrosis / metabolism

Substances

Apolipoproteins E
Apoo protein, mouse