由RIPK1 / RIPK3 / MLKL介导的角质形成细胞坏死的抑制提供了针对银屑病炎症的保护作用。,Cell Death & Disease

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由RIPK1 / RIPK3 / MLKL介导的角质形成细胞坏死的抑制提供了针对银屑病炎症的保护作用。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-02-19 , DOI: 10.1038/s41419-020-2328-0
Xiaoru Duan ₁ , Xinxin Liu ₁ , Nian Liu ₁ , Yuqiong Huang ₁ , Zilin Jin ₁ , Song Zhang ₁ , Zhangyin Ming ₂ , Hongxiang Chen _{1,

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牛皮癣是一种常见的自身免疫和慢性炎症性皮肤病，全球影响0.51-11.43％的成年人。角质形成细胞中与炎症相关的细胞死亡在牛皮癣的炎症级联反应中起着关键作用。坏死性坏死是由受体相互作用蛋白激酶1（RIPK1），RIPK3和混合谱系激酶结构域样假激酶（MLKL）介导的坏死性细胞死亡，它参与了许多人类炎症性疾病。然而，牛皮癣中的程序性坏死的机制和功能没有很好地说明。在当前的研究中，我们为银屑病坏死病的发生提供了证据。RIPK1和MLKL在人银屑病皮损的表皮各层均显着上调和定位，而RIPK3和磷酸化MLKL主要在角质形成细胞中表达，位于上层。在IMQ诱导的小鼠牛皮癣样皮肤中还发现了坏死病的增加趋势。此外，我们发现RIPK1 R-7-Cl-O-Necrostatin-1（Nec-1s）抑制剂和MLKL抑制剂necrosulfonamide（NSA）均能抑制HaCaT细胞和IMQ小鼠模型中的坏死病，从而有效阻断IMQ诱导的炎症体内反应，并显着下调炎症因子如IL-1β，IL-6，IL-17A，IL-23a，CXCL1和CCL20的产生。这些发现促进了新的疗法的发展，用于治疗死皮病激活的牛皮癣的病理。我们发现RIPK1 R-7-Cl-O-Necrostatin-1（Nec-1s）抑制剂和MLKL抑制剂necrosulfonamide（NSA）均能抑制HaCaT细胞和IMQ小鼠模型中的坏死病，在IMQ小鼠模型中有力地阻断了IMQ诱导的炎症反应在体内，并显着下调炎症因子如IL-1β，IL-6，IL-17A，IL-23a，CXCL1和CCL20的产生。这些发现促进了新的疗法的发展，用于治疗死皮病激活的牛皮癣的病理。我们发现RIPK1 R-7-Cl-O-Necrostatin-1（Nec-1s）抑制剂和MLKL抑制剂necrosulfonamide（NSA）均能抑制HaCaT细胞和IMQ小鼠模型中的坏死病，在IMQ小鼠模型中有力地阻断了IMQ诱导的炎症反应在体内，并显着下调炎症因子如IL-1β，IL-6，IL-17A，IL-23a，CXCL1和CCL20的产生。这些发现促进了新的疗法的发展，用于治疗死皮病激活的牛皮癣的病理。

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Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation.

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-1β, 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.

更新日期：2020-02-19

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