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TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis

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收录情况： ◇ SCIE

作者：
Kong Xiangzhen[1] * ; Jiang Shuai[2] * ; He Qiuyu[1] ; Shi Xiangguang[3] ; Pu Weilin[4] ; Huang Yan[1] ; Ma Yanyun[5,6] ; Liu Qingmei[3] ; Sun Dayan[7] ; Huang Delin[1] ; Wu Fei[1] ; Li Pengcheng[8] ; Tu Wenzhen[9] ; Zhao Yinhuan[9] ; Wang Lei[9] ; Chen Yuanyuan[9] ; Wu Wenyu[3] ; Tang Yulong[1] ; Zhao Xiansheng[10] ; Zhu Qing[11] ; Gao Jian[1,12] ; Xu Weihong[13] ; Shui Xiaochuan[14] ; Qian Feng[12,*2] ; Wang Jiucun[1,15,16,*1] ;
机构： [1]State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China. [2]Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai, China. [3]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. [4]Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou, China. [5]Institute for Six-sector Economy, Fudan University, Shanghai, China. [6]Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China. [7]Department of Neonatal Surgery, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China. [8]Department of Pancreatic Surgery, Fudan University Cancer Hospital, Shanghai, China. [9]Division of Rheumatology, Shanghai Integrated Traditional Chinese and Western Medicine Hospital, Shanghai, China. [10]Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. [11]Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [12]Ministry of Education Key Laboratory of Contemporary Anthropology, Zhangjiang Fudan International Innovation Center, Human Phenome Institute and School of Life Sciences, Fudan University, Shanghai, China. [13]Laboratory Department of Tongren Hospital Affiliated to Medical College of Shanghai Jiaotong University, Shanghai, China. [14]Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China. [15]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China. [16]Institute of Rheumatology, Immunology, and Allergy, Fudan University, Shanghai, China.
出处：
DOI： 10.1093/rheumatology/kead456
ISSN：

关键词： TLR8 skin fibroblasts SSc inflammation fibrosis

摘要：
Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc.The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model.TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1β, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo.TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

基金：
This study was supported by the National Natural Science Foundation of China (82030003, 82000070); the CAMS Innovation Fund for Medical Sciences (2019-I2M-5–066); and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).
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外文
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中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 2 区 风湿病学
最新[2023]版：
大类 | 2 区 医学
小类 | 2 区 风湿病学
JCR分区：
出版当年[2022]版：
Q1 RHEUMATOLOGY
最新[2023]版：
Q1 RHEUMATOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

第一作者：
第一作者机构： [1]State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China. [12]Ministry of Education Key Laboratory of Contemporary Anthropology, Zhangjiang Fudan International Innovation Center, Human Phenome Institute and School of Life Sciences, Fudan University, Shanghai, China. [15]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China. [16]Institute of Rheumatology, Immunology, and Allergy, Fudan University, Shanghai, China. [*1]School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, People’s Republic of China [*2]Ministry of Education Key Laboratory of Contemporary Anthropology, Zhangjiang Fudan International Innovation Center, Human Phenome Institute and School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, People’s Republic of China
推荐引用方式(GB/T 7714)：
Kong Xiangzhen,Jiang Shuai,He Qiuyu,et al.TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis[J].RHEUMATOLOGY.2024,63(6):1710-1719.doi:10.1093/rheumatology/kead456.
APA：
Kong Xiangzhen,Jiang Shuai,He Qiuyu,Shi Xiangguang,Pu Weilin...&Wang Jiucun.(2024).TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.RHEUMATOLOGY,63,(6)
MLA：
Kong Xiangzhen,et al."TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis".RHEUMATOLOGY 63..6(2024):1710-1719

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