CD163 deficiency increases foam cell formation and plaque progression in atherosclerotic mice
CD163 deficiency increases foam cell formation and plaque progression in atherosclerotic mice
复制标题
DOI：
10.1096/fj.202000177r
复制
发表时间：
2020-09-14
期刊：
影响因子：
4.8
通讯作者：
Blanco-Colio, Luis M.
中科院分区：
文献类型：
--
作者：
Gutierrez-Munoz, Carmen;Mendez-Barbero, Nerea;Blanco-Colio, Luis M.
动脉粥样硬化是一种炎症性疾病，其特征在于巨噬细胞在血管壁中的积聚。巨噬细胞依赖于它们的极化来发挥促炎或抗炎作用。抗炎表型的巨噬细胞表达高水平的CD 163，一种血红蛋白-触珠蛋白复合物的清道夫受体。CD 163还可以结合促炎细胞因子TWEAK。我们使用ApoE缺陷或ApoE/CD 163双缺陷小鼠研究CD 163在动脉粥样硬化发展中的作用及其中和TWEAK作用的能力。ApoE/CD 163双缺陷小鼠表现出更不稳定的斑块表型，其特征是脂质和巨噬细胞含量增加，斑块大小和促炎细胞因子表达增加。体外实验表明，M2型巨噬细胞中CD 163的缺乏通过上调CD 36表达诱导泡沫细胞形成。此外，与ApoE（-/-）/CD 163（+/+）小鼠相比，外源性TWEAK给药增加了ApoE（-/-）/CD 163（-/-）小鼠的动脉粥样硬化病变大小、脂质和巨噬细胞含量。重组CD 163治疗能够中和ApoE/CD 163双缺陷小鼠中TWEAK的致动脉粥样硬化作用。重组CD 163消除了TWEAK对血管平滑肌细胞的促炎作用，降低了NF-κ B活化、细胞因子和金属蛋白酶表达以及巨噬细胞迁移。总之，表达CD 163的巨噬细胞作为一种保护机制，以防止TWEAK对动脉粥样硬化斑块的发展和进展的有害影响。
Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the vessel wall. Macrophages depend on their polarization to exert either pro-inflammatory or anti-inflammatory effects. Macrophages of the anti-inflammatory phenotype express high levels of CD163, a scavenger receptor for the hemoglobin-haptoglobin complex. CD163 can also bind to the pro-inflammatory cytokine TWEAK. UsingApoE-deficient orApoE/CD163double-deficient mice we aim to investigate the involvement of CD163 in atherosclerosis development and its capacity to neutralize the TWEAK actions.ApoE/CD163double-deficient mice displayed a more unstable plaque phenotype characterized by an increased lipid and macrophage content, plaque size, and pro-inflammatory cytokine expression. In vitro experiments demonstrated that the absence of CD163 in M2-type macrophages-induced foam cell formation through upregulation of CD36 expression. Moreover, exogenous TWEAK administration increased atherosclerotic lesion size, lipids, and macrophages content inApoE(-/-)/CD163(-/-)compared withApoE(-/-)/CD163(+/+)mice. Treatment with recombinant CD163 was able to neutralize the proatherogenic effects of TWEAK inApoE/CD163 double-deficient mice. Recombinant CD163 abolished the pro-inflammatory actions of TWEAK on vascular smooth muscle cells, decreasing NF-kB activation, cytokines and metalloproteinases expression, and macrophages migration. In conclusion, CD163-expressing macrophages serve as a protective mechanism to prevent the deleterious effects of TWEAK on atherosclerotic plaque development and progression.