Activation of STING signaling accelerates skin wound healing
Activation of STING signaling accelerates skin wound healing
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DOI：
10.1016/j.jdermsci.2019.11.008
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发表时间：
2020-01-01
影响因子：
4.6
通讯作者：
Seishima, Mariko
中科院分区：
文献类型：
--
作者：
Mizutani, Yuki;Kanbe, Ayumu;Seishima, Mariko
背景：皮肤损伤后的修复过程受到细胞因子和趋化因子等多种介质的精确调控。最近的研究表明，胞质DNA传感器环状GMP-AMP合成酶(CGAS)通过产生环状GMP-AMP(CGAMP)来激活干扰素基因刺激物(STING)，进而诱导炎性细胞因子，包括I型干扰素(IFN)。目的：探讨cGAMP激活STING通路是否影响皮肤创伤修复过程。方法：采用野生型(WT)小鼠建立皮肤创伤修复模型。两个全层皮肤活检分别取自右侧和左侧肩胛骨下区域。其中一处用含有cGAMP的软膏治疗，另一处用对照软膏治疗。结果：cGAMP可显著促进创面愈合至第6天。生化分析显示，局部应用cGAMP可促进创面刺痛信号转导通路，并能显著增强cGAMP处理创面中干扰素-β、CXCL10和CCL2的表达。划痕试验还显示cGAMP处理促进了小鼠胚胎成纤维细胞的伤口闭合。抗IFNR抗体和抗CXCR3抗体可抑制cGAMP对WT小鼠皮肤创面修复的促进作用。结论：外用cGAMP可通过诱导I型干扰素和CXCL10/CXCR3促进皮肤创面愈合。局部应用cGAMP可能有助于加速皮肤创面愈合的新的有效治疗方法。(C)2019年，爱思唯尔公司代表日本皮肤病研究学会出版。
Background: The process of repair after skin injury is precisely regulated by a variety of mediators such as cytokines and chemokines. Recent reports demonstrated that cytoplasmic DNA-sensor cyclic GMP-AMP synthase (cGAS) activates the stimulator of interferon genes (STING) via production of cyclic GMP-AMP (cGAMP) and subsequently induces inflammatory cytokines, including type I interferon (IFN).Objective: We examined whether activation of the STING pathway by cGAMP affects the process of skin wound repair. Methods: The skin wound repair model was established using wild-type (WT) mice. Two full-thickness skin biopsies were taken from the right and left subscapular regions. One site was treated with ointment containing cGAMP, and the other was treated with a control ointment. Changes in wound size over time were calculated using photography.Results: Treatment with cGAMP significantly accelerated skin wound healing up to day 6. Biochemical analyses showed that topical treatment with cGAMP on wound sites promoted STING signaling pathway and enhanced the expression of IFN-beta,CXCL10 and CCL2 in the wound sites treated with cGAMP markedly compared with the control. The scratch assay also revealed that cGAMP treatment accelerated wound closure in mouse embryonic fibroblasts. The acceleration of skin wound repair by cGAMP in WT mouse was impaired by administration of anti-IFNR antibody and anti-CXCR3 antibody respectively.Conclusion: These results revealed that topical treatment with cGAMP accelerates skin wound healing by inducing type I IFN and CXCL10/CXCR3. Topical administration of cGAMP might contribute to new effective treatments for accelerating skin wound healing. (C) 2019 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.