Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis.
Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis.
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DOI：
10.1159/000534639
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发表时间：
2023
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
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银屑病是一种常见的炎症性皮肤病，表皮角质形成细胞既是皮肤银屑病免疫反应的反应者，又是皮肤免疫反应的加速器，在银屑病发病机制中起着至关重要的作用。晚期糖基化终末产物(AGEs)是一类促炎代谢物，通常在心脏代谢紊乱中蓄积。最近的研究也观察到银屑病患者血清和皮肤中AGEs水平的升高，但AGEs在银屑病炎症中的作用尚未得到很好的研究。在目前的研究中，我们最初检测到银屑病患者皮损的表皮角质形成细胞中AGEs的异常积聚。此外，AGEs通过上调角蛋白17(K17)介导的p27KIP1抑制作用促进角质形成细胞的增殖，进而加速细胞周期进程。更重要的是，AGEs促进角质形成细胞产生白介素36α(IL-36α)，从而增强辅助性T细胞(Th17)的免疫应答。此外，AGEs对角质形成细胞中K17和IL-36α的诱导依赖于信号转导和转录激活因子1/3(STAT1/3)信号通路的激活。最后，AGEs对角质形成细胞的作用是通过AGEs受体(RAGE)介导的。综上所述，这些发现支持AGEs增强角质形成细胞的天然免疫功能，这有助于银屑病炎症的形成。我们的研究表明，AGEs是牛皮癣和心脏代谢性共病之间潜在的致病联系。
Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.
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