CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis

Autor: Yanmei Cui, Haiyong Wu, Zhihang Liu, Tenghui Ma, Wenfeng Liang, Qingzhi Zeng, Daici Chen, Qiyuan Qin, Binjie Huang, Michael Hu Wang, Xiaoyan Huang, Yanjiong He, Yingyi Kuang, Shinya Sugimoto, Toshiro Sato, Lei Wang
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Pathology. 259:180-193
ISSN: 1096-9896
0022-3417
DOI: 10.1002/path.6031
Popis: Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease and so far, there is no specific targeted therapy. Here, we report that CXCL16 is up-regulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis, and meanwhile to transcriptionally modulate the levels of BMP4 and HGF in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE, and suggest that CXCL16 signaling could be a potential therapeutic target for RE. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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