Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice.
Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice.
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DOI：
10.3389/fcell.2020.592048
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发表时间：
2020
影响因子：
5.5
通讯作者：
Li HH
中科院分区：
文献类型：
--
作者：
Liao J;An X;Yang X;Lin QY;Liu S;Xie Y;Bai J;Xia YL;Li HH
巨噬细胞极化和炎症是动脉粥样硬化发生和进展的关键因素。免疫蛋白酶体复合物由三个诱导型催化亚基（LMP2、LMP10 和 LMP7）组成，它们在这些危险因素的调节中发挥着关键作用。我们最近证明，LMP7 亚基通过抑制 MERTK 介导的胞吞作用促进饮食诱导的动脉粥样硬化。在这里，我们探索了LMP10的另一个亚基在疾病过程中的作用，使用ApoE敲除（ko）小鼠作为体内动脉粥样硬化模型，饲喂含有0.5％胆固醇和20％脂肪的致动脉粥样硬化饮食（ATD）8周。我们观察到 ATD 显着上调主动脉病变中 LMP10 的表达，这些病变主要与斑块巨噬细胞共定位。相反，LMP10的缺失显着减弱了动脉粥样硬化病变区域、CD68+巨噬细胞积聚和斑块中的坏死核心扩张，但没有改变血浆代谢参数、病变SM22α+平滑肌细胞或胶原含量。通过骨髓移植对 LMP10 进行髓系特异性缺失会导致相似的表型。此外，LMP10的缺失显着减少了主动脉巨噬细胞浸润并增加了M2/M1比率，伴随着促炎M1细胞因子（MCP-1、IL-1和IL-6）表达减少和抗炎M2细胞因子（IL-4和IL-10）表达增加。此外，我们在培养的巨噬细胞中证实，在体外 ox-LDL 诱导的泡沫细胞形成过程中，LMP10 缺失会减弱巨噬细胞的极化和炎症，这与 IκBα 降解和 NF-κB 激活的减少有关。我们的结果表明，免疫蛋白酶体亚基 LMP10 可能通过调节 NF-κB 介导的巨噬细胞极化和炎症来促进 ApoE ko 小鼠饮食诱导的动脉粥样硬化。靶向 LMP10 可能代表动脉粥样硬化的新治疗方法。
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.