炎症
巨噬细胞极化
传出细胞增多
巨噬细胞
载脂蛋白E
泡沫电池
川地68
内分泌学
M2巨噬细胞
化学
内科学
医学
促炎细胞因子
脂多糖
肿瘤坏死因子α
载脂蛋白B
生物
免疫学
基因剔除小鼠
脂蛋白
胆固醇
转基因小鼠
体外
生物化学
免疫组织化学
疾病
作者
Jiawei Liao,Xiangbo An,Xiaolei Yang,Qiu-Yue Lin,Shuang Liu,Yunpeng Xie,Jie Bai,Yunlong Xia,Huihua Li
标识
DOI:10.3389/fcell.2020.592048
摘要
Macrophage polarization and inflammation are key factors for the onset and progression of atherosclerosis. The immunoproteasome complex consists of three inducible catalytic subunits (LMP2, LMP10, and LMP7) that play a critical role in the regulation of these risk factors. We recently demonstrated that the LMP7 subunit promotes diet-induced atherosclerosis via inhibition of MERTK-mediated efferocytosis. Here, we explored the role of another subunit of LMP10 in the disease process, using ApoE knockout (ko) mice fed on an atherogenic diet (ATD) containing 0.5% cholesterol and 20% fat for 8 weeks as an in vivo atherosclerosis model. We observed that ATD significantly upregulated LMP10 expression in aortic lesions, which were primarily co-localized with plaque macrophages. Conversely, deletion of LMP10 markedly attenuated atherosclerotic lesion area, CD68+ macrophage accumulation, and necrotic core expansion in the plaques, but did not change plasma metabolic parameters, lesional SM22α+ smooth muscle cells, or collagen content. Myeloid-specific deletion of LMP10 by bone marrow transplantation resulted in similar phenotypes. Furthermore, deletion of LMP10 remarkably reduced aortic macrophage infiltration and increased M2/M1 ratio, accompanied by decreased expression of pro-inflammatory M1 cytokines (MCP-1, IL-1, and IL-6) and increased expression of anti-inflammatory M2 cytokines (IL-4 and IL-10). In addition, we confirmed in cultured macrophages that LMP10 deletion blunted macrophage polarization and inflammation during ox-LDL-induced foam cell formation in vitro, which was associated with decreased IκBα degradation and NF-κB activation. Our results show that the immunoproteasome subunit LMP10 promoted diet-induced atherosclerosis in ApoE ko mice possibly through regulation of NF-κB-mediated macrophage polarization and inflammation. Targeting LMP10 may represent a new therapeutic approach for atherosclerosis.
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