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.

中文翻译：

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巨噬细胞来源的 IL-10 通过上皮 WISP-1 信号介导粘膜修复

为了应对损伤，上皮细胞迁移和增殖以覆盖裸露的粘膜表面并修复屏障缺陷。这个过程是由免疫细胞和上皮细胞之间的动态串扰协调的；然而，所涉及的机制仍未完全了解。在这里，我们报告说，IL-10 在肠粘膜损伤后被迅速诱导，并且是最佳肠粘膜伤口闭合所必需的。在体内条件性缺失表达 CD11c 的细胞中的 IL-10 表明巨噬细胞是 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，T 细胞和 B 细胞缺陷型Rag1 的伤口闭合^–/–小鼠没有受到损伤，表明适应性免疫细胞并不是这个过程所必需的。此外，在粘膜损伤后，巨噬细胞衍生的 IL-10 导致上皮 cAMP 反应元件结合蛋白 (CREB) 激活，随后合成和分泌促修复 WNT1 诱导信号蛋白 1 (WISP-1)。WISP-1 通过激活上皮促增殖途径诱导上皮细胞增殖和伤口闭合。这些发现确定了巨噬细胞参与调节 IL-10/CREB/WISP-1 信号轴，在将先天免疫激活与粘膜伤口修复联系起来方面具有广泛意义。