CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling.

IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Fan Xu, Ying-Zhe Cui, Xing-Yu Yang, Yu-Xin Zheng, Xi-Bei Chen, Hao Zhou, Zhao-Yuan Wang, Yuan Zhou, Yi Lu, Ying-Ying Li, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Xue-Yan Chen, Min Zheng, Yong Yang, Xiao-Yong Man
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Abstract

Psoriatic arthritis (PsA) is a multifaceted chronic inflammatory disease affecting the skin, joints, and entheses, and is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement, however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermal-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2-STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF𝜶 production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1-CXCL10-periarticular CD14hi macrophages-TNFα axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.

由spry1缺失的表皮角质形成细胞分泌的CXCL10通过CD14信号通路促进银屑病关节炎的关节炎症。
银屑病关节炎(Psoriatic arthritis, PsA)是一种影响皮肤、关节和关节的多方面慢性炎症性疾病,是银屑病的主要合并症。大多数患有PsA的患者在关节受累之前就表现为银屑病,然而,皮肤银屑病和PsA之间的分子和细胞机制尚不清楚。在这里,我们发现表皮特异性spry1缺陷小鼠自发发生涉及皮肤和关节的psa样炎症。spry1缺失的表皮角质形成细胞通过增强JAK1/2-STAT1信号的激活分泌过量的CXCL10,并且CXCL10阻断可减弱psa样炎症。值得注意的是,CXCL10被发现与CD14结合,而不是CXCR3,通过PI3K/AKT和NF-κB信号通路促进关节周围CD14hi巨噬细胞TNF𝜶的产生。总之,本研究揭示表皮中SPRY1的缺乏足以驱动皮肤和关节炎症,并确定角化细胞来源的CXCL10和关节周围的CD14hi巨噬细胞是导致PsA的皮肤-关节串串的关键环节。这个角化细胞spry1 - cxcl10 -关节周CD14hi巨噬细胞- tnf α轴为银屑病向PsA转变的机制提供了有价值的见解,并提出了预防这一进展的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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