Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling
Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling
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DOI：
10.1172/jci90229
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发表时间：
2017-09-01
影响因子：
15.9
通讯作者：
Nusrat, Asma
中科院分区：
文献类型：
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作者：
Quiros, Miguel;Nishio, Hikaru;Nusrat, Asma
作为对损伤的反应，上皮细胞迁移和增殖以覆盖剥离的粘膜表面并修复屏障缺陷。这一过程是通过免疫细胞和上皮细胞之间的动态串扰来协调的；然而，涉及的机制仍然不完全清楚。在这里，我们报告了IL-10在肠粘膜损伤后被迅速诱导，并是最佳肠黏膜伤口闭合所必需的。体内表达CD11c的细胞中特异性IL-10的条件性缺失意味着巨噬细胞是IL-10诱导的伤口闭合的关键先天免疫贡献者。与这些发现一致的是，T细胞和B细胞缺陷的Rag1(-/-)小鼠的伤口闭合没有受到损害，表明适应性免疫细胞并不是这一过程绝对需要的。此外，在粘膜损伤后，巨噬细胞来源的IL-10导致上皮cAMP反应元件结合蛋白(CREB)的激活，随后合成和分泌促进修复的WNT1诱导的信号蛋白1(WSAP-1)。WISP-1通过激活上皮细胞促增殖通路，诱导上皮细胞增殖和伤口闭合。这些发现明确了巨噬细胞参与调节IL-10/CREB/WISP-1信号轴，并在将天然免疫激活与粘膜伤口修复联系起来方面具有广泛的意义。
In response to injury, epithelial cells migrate and proliferate to cover denuded mucosal surfaces and repair the barrier defect. This process is orchestrated by dynamic crosstalk between immune cells and the epithelium; however, the mechanisms involved remain incompletely understood. Here, we report that IL-10 was rapidly induced following intestinal mucosal injury and was required for optimal intestinal mucosal wound closure. Conditional deletion of IL-10 specifically in CD11c-expressing cells in vivo implicated macrophages as a critical innate immune contributor to IL-10-induced wound closure. Consistent with these findings, wound closure in T cell-and B cell-deficient Rag1(-/-) mice was unimpaired, demonstrating that adaptive immune cells are not absolutely required for this process. Further, following mucosal injury, macrophage-derived IL-10 resulted in epithelial cAMP response element-binding protein (CREB) activation and subsequent synthesis and secretion of the pro-repair WNT1-inducible signaling protein 1 (WISP-1). WISP-1 induced epithelial cell proliferation and wound closure by activating epithelial pro-proliferative pathways. These findings define the involvement of macrophages in regulating an IL-10/CREB/WISP-1 signaling axis, with broad implications in linking innate immune activation to mucosal wound repair.