Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
Mucosal Immunol. 2019 Jul;12(4):909-918. doi: 10.1038/s41385-019-0150-8. Epub 2019 Apr 10.
Pathobiology of several chronic inflammatory disorders, including ulcerative colitis and Crohn's disease is related to intermittent, spontaneous injury/ulceration of mucosal surfaces. Disease morbidity has been associated with pathologic release of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). In this report, we show that TNFα promotes intestinal mucosal repair through upregulation of the GPCR platelet activating factor receptor (PAFR) in the intestinal epithelium. Platelet activating factor (PAF) was increased in healing mucosal wounds and its engagement with epithelial PAFR leads to activation of epidermal growth factor receptor, Src and Rac1 signaling to promote wound closure. Consistent with these findings, delayed colonic mucosal repair was observed after administration of a neutralizing TNFα antibody and in mice lacking PAFR. These findings suggest that in the injured mucosa, the pro-inflammatory milieu containing TNFα and PAF sets the stage for reparative events mediated by PAFR signaling.
几种慢性炎症性疾病的发病机制，包括溃疡性结肠炎和克罗恩病，与黏膜表面间歇性、自发性损伤/溃疡有关。疾病发病率与促炎细胞因子肿瘤坏死因子-α（TNFα）的病理性释放有关。在本报告中，我们表明 TNFα 通过在上皮细胞中上调 GPCR 血小板激活因子受体（PAFR）促进肠道黏膜修复。血小板激活因子（PAF）在愈合的黏膜伤口中增加，其与上皮细胞 PAFR 的结合导致表皮生长因子受体、Src 和 Rac1 信号的激活，从而促进伤口闭合。这些发现表明，在受损的黏膜中，含有 TNFα 和 PAF 的促炎环境为 PAFR 信号介导的修复事件奠定了基础。
