Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
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抑制 RIPK1/RIPK3/MLKL 介导的角质细胞坏死性凋亡可提供针对银屑病炎症的保护作用
DOI：
10.1038/s41419-020-2328-0
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发表时间：
2020-02-19
影响因子：
9
通讯作者：
Chen, Hongxiang
中科院分区：
文献类型：
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作者：
Duan, Xiaoru;Liu, Xinxin;Chen, Hongxiang
银屑病是一种常见的自身免疫性和慢性炎症性皮肤病，全球影响0.51-11.43%的成年人。角质形成细胞的炎症相关性细胞死亡在银屑病的炎症级联反应中起着关键作用。坏死性凋亡是由受体相互作用蛋白激酶1（RIPK 1）、RIPK 3和混合谱系激酶结构域样假激酶（MLKL）介导的调节性坏死细胞死亡，其参与许多人类炎症性疾病。然而，程序性坏死在银屑病中的机制和作用还没有很好的阐明。在目前的研究中，我们提供的证据参与坏死性凋亡银屑病。RIPK 1和MLKL在人银屑病皮损中表达显著上调，并定位于表皮的所有层，而RIPK 3和磷酸化的MLKL主要表达于角质形成细胞，位于上层。在IMQ诱导的小鼠银屑病样皮肤中也发现了坏死性凋亡增加的趋势。此外，我们发现RIPK 1 R-7-Cl-O-Necrostatin-1（Nec-1 s）抑制剂和MLKL抑制剂necrosulfonamide（NSA）均可抑制HaCaT细胞和IMQ小鼠模型中的坏死性凋亡，有效阻断IMQ诱导的体内炎症反应，并显著下调炎症因子如IL-1 β、IL-6、IL-17 A、IL-23 a、CXCL 1和CCL 20的产生。这些研究结果促进了新疗法的发展，用于治疗坏死性银屑病激活的病理。
Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51-11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1 beta, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.