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

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

Author information

1
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
2
Department of Pathology, Emory University, Atlanta, Georgia, USA.
3
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
4
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University (LMU) Munich, Munich, Germany.
5
Department of Internal Medicine and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
6
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.

Abstract

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.

PMID:
28783045
PMCID:
PMC5669557
DOI:
10.1172/JCI90229
[Indexed for MEDLINE]
Free PMC Article

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