Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling
Miguel Quiros ... Timothy L. Denning, Asma Nusrat
Miguel Quiros ... Timothy L. Denning, Asma Nusrat
Published September 1, 2017
Citation Information: J Clin Invest. 2017;127(9):3510-3520. doi:10.1172/JCI90229.
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Categories: Research Article Immunology Inflammation

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

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.

Authors

Miguel Quiros, Hikaru Nishio, Philipp A. Neumann, Dorothee Siuda, Jennifer C. Brazil, Veronica Azcutia, Roland Hilgarth, Monique N. O’Leary, Vicky Garcia-Hernandez, Giovanna Leoni, Mingli Feng, Gabriela Bernal, Holly Williams, Priya H. Dedhia, Christian Gerner-Smidt, Jason Spence, Charles A. Parkos, Timothy L. Denning, Asma Nusrat

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Figure 2

Macrophage-derived IL-10 promotes intestinal mucosal wound healing.

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Macrophage-derived IL-10 promotes intestinal mucosal wound healing. (A) ...
(A) Endoscopic images of healing colonic mucosal wounds 1 and 3 days after biopsy-induced injury in Il10–/– versus Il10+/+ mice and quantification of wound repair (***P < 0.001; n = 5 mice, average of 3 wounds, mean ± SEM). (B and C) Endoscopic images of healing colonic mucosal wounds 1 and 3 days after biopsy-induced injury in Rag1–/– versus Rag1+/+ mice and IL-10fl/flCD11c Cre versus IL-10fl/fl mice and quantification of wound repair (***P < 0.001, n = 5 mice, average of 3 wounds, mean ± SEM). (D) Il10 mRNA levels in intact colonic tissue and day-2 post-injury wounds in IL-10fl/flCD11c Cre and IL-10fl/fl mice (***P < 0.001, n = 5, mean ± SEM). (E) Confocal micrographs of punch biopsies from IL-10 GFP reporter mice with resealing colonic wounds (2 days after injury) showing staining for GFP, F4/80, F-actin (phalloidin), and nuclei. Scale bar: 20 μm. Original magnification, ×40. White asterisks highlight IL-10–GFP colocalization with the macrophage marker F4-80. (F) Il10 mRNA–normalized levels of immune cells isolated from wounded LP colonic tissue on different post-injury days and intact tissue (*P < 0.05 and ***P < 0.001; n = 5 mice, image is representative of 2 separate experiments, mean ± SEM). (G and H) Representative plots of LP myeloid cells isolated from intact and wounded tissue from IL-10fl/fl and IL-10fl/flCD11c Cre mice and stained for Ly6C and F4/80 (n = 10, mean ± SEM). All statistical comparisons were performed using ANOVA with Tukey’s multiple comparisons post test. WD1, 1 day after wounding; WD3, 3 days after wounding.