Adipocyte-Derived CTRP3 Exhibits Anti-Inflammatory Effects via LAMP1-STAT3 Axis in Psoriasis
Adipocyte-Derived CTRP3 Exhibits Anti-Inflammatory Effects via LAMP1-STAT3 Axis in Psoriasis
复制标题
脂肪细胞衍生的 CTRP3 通过 LAMP1-STAT3 轴在银屑病中表现出抗炎作用
DOI：
10.1016/j.jid.2021.09.027
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发表时间：
2022
影响因子：
6.5
通讯作者：
Gang Wang
中科院分区：
文献类型：
--
作者：
Ke Xue;Shuai Shao;Hui Fang;Lirong Ma;Caixia Li;Zifan Lu;Gang Wang
牛皮癣是一种与代谢紊乱相关的全身性疾病，可能导致脂肪因子水平异常。然而，其根本机制在很大程度上尚不清楚。在这里，我们研究了脂肪因子 CTRP3 在银屑病和合并症发病机制中的作用。银屑病患者的循环 CTRP3 水平显着低于健康对照，且与代谢危险因素呈负相关。在饮食诱导的肥胖小鼠中，使用 GLP-1 受体激动剂 exendin-4 来恢复 CTRP3 水平，可以减轻咪喹莫特诱导的小鼠模型中更严重的银屑病症状。局部应用CTRP3也对咪喹莫特诱导的正常饮食小鼠产生保护作用。此外，CTRP3 可以在体外通过 LAMP1 阻断信号转导子和转录激活子 3 的磷酸化，从而直接抑制银屑病角质形成细胞的炎症反应。我们确定了关键的银屑病细胞因子，包括 IL-17A 和 TNF-α，它们会损害脂肪细胞分化和足够的 CTRP3 分泌。总之，我们的研究表明，IL-17A 引起的脂肪细胞功能障碍和 CTRP3 水平低会加剧银屑病进展和相关代谢综合征，这暗示着银屑病和代谢紊乱之间恶性循环的潜在机制。提高肥胖银屑病患者 CTRP3 水平的药物可被视为治疗银屑病的潜在策略。
Psoriasis is a systemic disease that is associated with metabolic disorders, which may contribute to abnormal adipokine levels. However, the underlying mechanism is largely unknown. Here, we investigated the role of the adipokine CTRP3 in the pathogenesis of psoriasis and comorbidities. The circulating CTRP3 level in patients with psoriasis was significantly lower than that in healthy controls and negatively correlated with metabolic risk factors. Rescuing CTRP3 levels with the GLP-1 receptor agonist exendin-4 in diet-induced obese mice could alleviate its more severe psoriatic symptoms in an imiquimod-induced mouse model. Topical application of CTRP3 also exerted a protective effect on imiquimod-induced normal diet mice. Moreover, CTRP3 could directly inhibit the inflammatory responses of psoriatic keratinocytes by blocking phosphorylation of signal transducer and activator of transcription 3 via LAMP1 in vitro. We identified the critical psoriatic cytokines, including IL-17A and TNF-α, that impaired adipocyte differentiation and sufficient CTRP3 secretion. In sum, our study reveals that adipocyte dysfunction and low level of CTRP3 caused by IL-17A exacerbates psoriasis progression and related metabolic syndrome, implying a mechanism underlying the vicious cycle between psoriasis and metabolic disorders. Pharmacological agents that improve CTRP3 level in obese patients with psoriasis may be considered as a potential strategy for psoriasis treatment.