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Updated: Jul 10, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Macrophage-specific deletion of MIC26 (APOO) mitigates advanced atherosclerosis by increasing efferocytosis
Xiaoyu Tang1, Zhijie Huang2, Fengjiao Wang2
1Department 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.
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.
Insights
Mice lacking MIC26 in macrophages showed reduced atherosclerosis by enhancing efferocytosis, a process linked to altered mitochondrial structure and OPA1 levels. This finding offers a potential therapeutic target for inflammatory diseases.
Area of Science:
- Mitochondrial biology
- Immunology
- Cardiovascular research
Background:
- MIC26 (apolipoprotein O, APOO) is a novel mitochondrial inner membrane protein implicated in inflammation.
- The role of macrophage MIC26 in acute inflammation and atherosclerosis was investigated.
Purpose of the Study:
- To investigate the role of macrophage MIC26 in acute inflammation and chronic inflammatory disease, atherosclerosis.
- To elucidate the underlying mechanisms by which MIC26 influences these processes.
Main Methods:
- Generated macrophage-specific MIC26 knockout mice (MIC26LysM).
- Utilized endotoxemia and atherosclerosis mouse models (MIC26LysM x Apoe-/- with Western diet).
- Analyzed atherosclerotic plaques, macrophage function, and mitochondrial structure/function.
Main Results:
- Macrophage MIC26 deficiency did not impact acute inflammation (endotoxemia).
- In atherosclerosis models, MIC26 deficiency reduced lesion size and necrotic core, and enhanced efferocytosis.
- Mechanistically, MIC26 loss led to abnormal mitochondrial structure, increased fission, decreased membrane potential, and reduced OPA1, promoting efferocytosis.
Conclusions:
- Macrophage MIC26 deletion alleviates atherosclerosis by promoting efferocytosis.
- This effect is linked to mitochondrial fission and reduced OPA1, suggesting a novel mechanism in atherosclerosis progression.
