Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis
Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis
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DOI：
10.1172/jci.insight.97179
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发表时间：
2018-01-11
期刊：
影响因子：
8
通讯作者：
Mehta, Nehal N.
中科院分区：
文献类型：
--
作者：
Baumer, Yvonne;Ng, Qimin;Mehta, Nehal N.
炎症是动脉粥样硬化形成的关键。牛皮癣是一种慢性炎症性皮肤病，会加速人类的动脉粥样硬化，并提供了一个令人信服的模型来了解这些疾病之间的潜在联系。捕捉牛皮癣血管和代谢性疾病的小鼠模型将加速我们的理解，并提供一个测试新疗法的平台。我们的目的是从心血管的角度描述一种新的小鼠皮肤炎症模型(Rac1V12)，以确定在慢性皮肤炎症中调节的新的动脉粥样硬化信号通路。RacV12牛皮癣小鼠类似于人类的疾病状态，包括全身炎症、血脂异常和心脏代谢功能障碍。银屑病巨噬细胞具有前动脉粥样硬化表型，脂质摄取增加，泡沫细胞形成，胆固醇晶体形成增加6倍。我们产生了一只三基因K14-racV12(-/+)/Srb1(-/-)/ApoER61(H/H)小鼠，并证实牛皮癣加速了动脉粥样硬化的形成(类似于7倍增加)。最后，我们注意到人银屑病巨噬细胞中超氧化物歧化酶2(SOD2)的表达减少了60%。当巨噬细胞中SOD2活性恢复时，其致动脉粥样硬化前表型逆转。我们证明，K14-racV12小鼠模型捕获了慢性炎症中观察到的心脏代谢功能障碍并加速了血管疾病，皮肤炎症诱导了SOD2功能受损的动脉粥样硬化前巨噬细胞表型，这与加速的动脉粥样硬化形成有关。
Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12(-/+)/Srb1(-/-)/ApoER61(H/H) mouse and confirmed psoriasis accelerates atherogenesis (similar to 7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.