ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils.
ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils.
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通过调节角质形成细胞及其与中性粒细胞的串扰，抑制 ULK1 作为银屑病的靶向治疗策略
DOI：
10.3389/fimmu.2021.714274
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发表时间：
2021
影响因子：
7.3
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Qiu X;Zheng L;Liu X;Hong D;He M;Tang Z;Tian C;Tan G;Hwang S;Shi Z;Wang L
银屑病是一种常见的炎症性皮肤病，由角质形成细胞和免疫细胞的相互作用引起。先前的研究已经确定了自噬在维持表皮稳态包括增殖和分化中的重要作用。然而，对自噬相关蛋白在皮肤免疫应答中的作用知之甚少。在此，我们发现，ULK1，关键的自噬启动子，其在Ser556磷酸化显着减少，在表皮从银屑病患者的皮损皮肤。局部应用选择性ULK1抑制剂SBI0206965可显著减弱咪喹莫特（IMQ）诱导的银屑病样皮炎（PsD）中的表皮增生、中性粒细胞浸润和银屑病相关标志物的转录。在体外实验中，ULK1的siRNA和SBI0206965的损害逮捕细胞增殖和促进角质形成细胞的凋亡，但在稳定状态下的促炎介质的表达有边际效应。令人惊讶的是，SBI0206965阻断了中性粒细胞刺激的角质形成细胞中趋化因子和细胞因子的产生。有趣的是，ULK1抑制的促凋亡和抗炎作用不能被自噬抑制剂完全复制。我们的研究结果表明，通过下调ULK1的自我调节过程，以维持银屑病皮肤的免疫稳态，通过调节角质形成细胞及其与中性粒细胞的串扰，可能通过自噬依赖和独立的机制。ULK1可能是预防或治疗银屑病的潜在靶点。
Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.
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影响因子：
4.6
作者：
Hu SC;Yu HS;Yen FL;Lin CL;Chen GS;Lan CC
通讯作者：
Lan CC
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1100123
发表时间：
2011-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lin AM;Rubin CJ;Khandpur R;Wang JY;Riblett M;Yalavarthi S;Villanueva EC;Shah P;Kaplan MJ;Bruce AT
通讯作者：
Bruce AT
DOI：
10.1111/febs.13356
发表时间：
2015-09
期刊：
The FEBS journal
影响因子：
--
作者：
Popelka H;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
4.4
作者：
Lee, Hye-Mi;Shin, Dong-Min;Jo, Eun-Kyeong
通讯作者：
Jo, Eun-Kyeong