Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling

J Clin Invest. 2017 Sep 1;127(9):3510-3520. doi: 10.1172/JCI90229. Epub 2017 Aug 7.


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.

MeSH terms

  • Animals
  • CCN Intercellular Signaling Proteins / metabolism*
  • CD11 Antigens / metabolism
  • Cell Proliferation
  • Colon / pathology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Gene Deletion
  • Gene Expression Regulation
  • Humans
  • Inflammation
  • Interleukin-10 / metabolism*
  • Intestinal Mucosa / metabolism
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction
  • Wound Healing


  • CCN Intercellular Signaling Proteins
  • CCN4 protein, human
  • CD11 Antigens
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • IL10 protein, human
  • Proto-Oncogene Proteins
  • Interleukin-10