CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis
CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis
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CXCL16在放射性肠炎进展过程中抑制上皮再生并促进纤维化
DOI：
10.1002/path.6031
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发表时间：
2022-12-12
影响因子：
7.3
通讯作者：
Wang, Lei
中科院分区：
文献类型：
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作者：
Cui, Yanmei;Wu, Haiyong;Wang, Lei
放射性肠炎(RE)是盆腔恶性肿瘤放射治疗的常见并发症，以严重的肠上皮破坏和进行性黏膜下纤维化为特征。然而，对这种疾病的发病机制知之甚少，到目前为止，还没有具体的靶向治疗方法。在这里，我们报告了CXCL16在RE患者受损的肠道组织和小鼠模型中上调。Cxcl16基因缺失减轻小鼠辐射损伤后的纤维化并促进肠干细胞介导的上皮再生。在机制上，CXCL16通过其受体CXCR6作用于肌成纤维细胞，激活JAK3/STAT3信号促进纤维化，同时转录调控肌成纤维细胞中BMP4和肝细胞生长因子(HGF)的水平。此外，我们发现CXCL16和CXCR6在正反馈环路中自我调节和交叉调节。CXCL16中和单抗治疗可减轻RE小鼠模型的纤维化，促进上皮修复。我们的研究结果强调了CXCL16在RE发生发展中的重要作用，并提示CXCL16信号通路可能成为RE的潜在治疗靶点。©2022大不列颠和爱尔兰病理学会。
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 upregulated 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, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (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. © 2022 The Pathological Society of Great Britain and Ireland.