Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center of Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
J Invest Dermatol. 2019 Mar;139(3):638-647. doi: 10.1016/j.jid.2018.09.021. Epub 2018 Oct 24.
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-17A mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17A and heterozygous CD11c-IL-17A 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.
除了皮肤炎症，严重银屑病患者还面临心血管死亡率增加的风险。IL-17A 在银屑病的发展中起核心作用，可能将皮肤和血管疾病联系起来。本研究旨在阐明抗 IL-17A 治疗是否也能改善与严重银屑病相关的血管功能障碍。我们分析了三种具有不同严重程度银屑病样皮肤疾病的小鼠模型，研究其血管功能和炎症情况：（i）K14-IL-17A 小鼠，其角蛋白细胞特异性过表达 IL-17A，具有早期严重银屑病样表型；（ii）CD11c-IL-17A 纯合子和 CD11c-IL-17A 杂合子小鼠，IL-17A 在 CD11c 细胞中过表达，导致中度银屑病样皮肤疾病延迟发生；（iii）咪喹莫特诱导的银屑病样皮肤炎症模型。与皮肤疾病的严重程度相似，血管功能障碍与外周 IL-17A 水平和中性粒细胞浸润主动脉血管壁相关。成功的抗 IL-17A 治疗银屑病皮损可降低外周氧化应激水平、促炎细胞因子和血管炎症。这些数据突出了 IL-17A 将皮肤病变和血管疾病联系起来在银屑病中的关键作用。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一种有效方法。
