三碘甲状腺原氨酸通过激活cGAS-STING信号通路调控炎症时相而促进小鼠皮肤伤口愈合  

Triiodothyronine promotes skin wound healing in mice by activating cGAS-STING signaling pathway and regulating inflammation phase

作　　者：殷菱 毛志蓉 吴俊丽 刘芳 高小青 YIN Ling;MAO Zhirong;WU Junli;LIU Fang;GAO Xiaoqing(Public Center of Experimental Technology&Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou,Southwest Medical University,Luzhou 646000,China;Department of Human Anatomy,School of Basic Medical Sciences,Southwest Medical University,Luzhou 646000,China)

机构地区：[1]西南医科大学公共实验技术中心,四川泸州646000 [2]血流动力学医工结合泸州市重点实验室,四川泸州646000

出　　处：《中国病理生理杂志》2025年第1期104-113,共10页Chinese Journal of Pathophysiology

基　　金：西南医科大学博士科研启动项目(No.66/00170036);2023年泸州市人民政府西南医科大学科技战略合作项目(No.2023LZXNYDPT004)。

摘　　要：目的:探讨三碘甲状腺原氨酸(T3)是否通过激活环磷酸鸟苷-磷酸腺苷酸合成酶(cGAS)-干扰素基因刺激物(STING)信号通路调控炎症时相从而影响小鼠皮肤伤口愈合。方法:将雄性昆明小鼠随机分为正常组、对照组、T3组、cGAS抑制剂RU320521(RU.521)组和RU.521+T3组,正常组5只,其余4组每组25只。除正常组外,其余各组小鼠制备全层皮肤损伤模型,每日观察伤口愈合情况。在伤后第1天,2天,4天,7天和10天分别处死各组小鼠,每组5只。苏木精-伊红(HE)和Masson染色分别观察小鼠皮肤伤口组织病理改变和胶原纤维形成;免疫组织化学染色观察cGAS、STING、小鼠含表皮生长因子样模体黏蛋白样激素受体样蛋白1(EMR1;又称F4/80)、C-XC趋化因子配体8(CXCL-8)和CXCL-10蛋白表达;Western blot检测cGAS、STING、C-C趋化因子配体2(CCL-2)和核因子κB(NF-κB)蛋白表达;ELISA法检测干扰素β(IFN-β)、白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)含量。结果:在伤后4~7 d,T3组的伤口愈合率和胶原纤维合成显著高于对照组、RU.521+T3组和RU.521组(P<0.05)。T3组的病理变化也较其余3组显著改善。正常组不表达cGAS和STING,RU.521+T3组和RU.521组表达也较少,而T3组和对照组表达较高,但T3组的表达在伤后1~4 d显著高于对照组(P<0.05),在伤后7 d低于对照组(P<0.05)。T3组F4/80的表达在伤后1~7 d显著高于对照组、RU.521+T3组和RU.521组(P<0.05)。此外,T3组的趋化因子CXCL-8、CXCL-10和CCL-2的表达在伤后1~2 d或1~4 d显著高于对照组、RU.521+T3组和RU.521组(P<0.05),在其余时间低于此3组(P<0.05)。除此之外,T3组的促炎细胞因子IFN-β、IL-6、TNF-α和NF-κB含量,在伤后1 d高于对照组、RU.521+T3组和RU.521组(P<0.05),而在伤后2~7 d显著低于这3组(P<0.05)。结论:T3促进小鼠皮肤伤口愈合可能与其在伤后早期加强cGAS-STING信号通路激活,增强趋化因子和促炎因子表达,以及促进巨噬细胞招募,从而调�AIM:This study aims to investigate whether triiodothyronine(T3)can enhance skin wound healing by activating the the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway to modulate the inflammatory phase.METHODS:Mice were randomly assigned to five groups:normal,control,T3,RU.521+T3,and RU.521(a cGAS inhibitor).With the exception of the normal group,a full-thickness skin defect model was established in the other groups.Wound healing was observed daily.Mice were euthanized on post-injury days 1,2,4,7,and 10,with five mice per group.Pathological changes and collagen fiber formation were assessed using hematoxylin-eosin(HE)and Masson staining,respectively.Immunohistochemical staining was performed to evaluate the expression of cGAS,STING,mouse EGF-like module-containing mucin-like hormone receptor-like 1(EMR1 or F4/80),C-X-C motif chemokine ligand 8(CXCL-8),and CXCL-10.Western blotting was conducted to measure protein levels of cGAS,STING,C-C motif chemokine ligand-2(CCL-2),and nuclear factor-κB(NF-κB).Enzyme linked immunosorbent assay(ELISA)was utilized to quantify the levels of interferon-β(IFN-β),interleukin-6(IL-6),and tumor necrosis factorα(TNF-α).RESULTS:From days 1 to 4 post-injury,the wound healing rate and collagen fiber formation in the T3 group were significantly greater than those in the control,RU.521+T3,and RU.521 groups(P<0.05).Additionally,the T3 group displayed more favorable pathological changes compared to the other groups.No expression of cGAS and STING was observed in the normal group,while low levels were found in the RU.521+T3 and RU.521 groups.The T3 and control groups exhibited higher expression levels,with the T3 group showing significantly elevated expression on days 1 to 4 post-injury(P<0.05)but lower expression on day 7 compared to the control group(P<0.05).The expression of the macrophage marker F4/80 was higher in the T3 group compared to the control,RU.521+T3,and RU.521 groups on days 1 to 7 post-injury(P<0.0

关 键 词：三碘甲状腺原氨酸 伤口愈合 cGAS-STING通路 炎症 巨噬细胞 趋化因子 

分 类 号：R363[医药卫生—病理学] R977.14[医药卫生—基础医学] R751