Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis.
Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis.
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DOI：
10.1016/j.jid.2018.09.021
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发表时间：
2019-03
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通讯作者：
Rebecca Schüler;A. Brand;Sabrina Klebow;J. Wild;F. Veras;Elisabeth Ullmann;S. Roohani;F. Kolbinger;Sabine Kossmann;C. Wohn;A. Daiber;T. Münzel;P. Wenzel;A. Waisman;B. Clausen;S. Karbach
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作者：
Rebecca Schüler;A. Brand;Sabrina Klebow;J. Wild;F. Veras;Elisabeth Ullmann;S. Roohani;F. Kolbinger;Sabine Kossmann;C. Wohn;A. Daiber;T. Münzel;P. Wenzel;A. Waisman;B. Clausen;S. Karbach
除了皮肤炎症，严重牛皮癣患者心血管死亡的风险增加。IL-17A在银屑病的发生发展中起核心作用，并可能将皮肤和血管疾病联系起来。这项研究的目的是阐明抗IL-17A治疗是否也可以改善与严重银屑病相关的血管功能障碍。我们分析了三种不同严重程度的银屑病样皮肤病小鼠模型的血管功能和炎症情况：(I)角质形成细胞特异性IL-17A过度表达的K14-IL-17Aind/+小鼠和早发性重度银屑病样表型；(Ii)CD11c-IL-17Aind/+纯合子和杂合子CD11c-IL-17Aind/+小鼠CD11c+细胞过度表达IL-17A，导致中度银屑病样皮肤病延迟发病；以及(Iii)吡喹莫德诱导的急性银屑病样皮肤炎症模型。与皮肤病的严重程度类似，血管功能障碍与外周IL-17A水平和中性粒细胞渗入主动脉管壁有关。成功的银屑病皮肤病变的抗IL-17A治疗降低了外周氧化应激水平、促炎细胞因子和血管炎症。这些数据突显了IL-17A在牛皮癣皮损和血管疾病发展过程中的关键作用。因此，抗IL-17A治疗可能是减轻和预防银屑病患者血管疾病的有效方法。
Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. IL-17A plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis. We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i)K14-IL-17Aind/+mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygousCD11c-IL-17Aind/indand heterozygousCD11c-IL-17Aind/+mice overexpressing IL-17A in CD11c+cells, leading to a delayed onset of moderate psoriasis-like skin disease; and (iii) the acute model of imiquimod-induced psoriasis-like skin inflammation. Similar to the severity of skin disease, vascular dysfunction correlated with peripheral IL-17A levels and neutrophil infiltration into the aortic vessel wall. Successful anti-IL-17A treatment of psoriatic skin lesions diminished peripheral oxidative stress levels, proinflammatory cytokines, and vascular inflammation. These data highlight the pivotal role of IL-17A linking the development of skin lesions and vascular disease in psoriasis. Anti-IL-17A therapy might thus represent a useful approach to attenuate and prevent vascular disease in psoriasis patients.