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 August 7, 2017
Citation Information: J Clin Invest. 2017;127(9):3510-3520. https://doi.org/10.1172/JCI90229.
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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 5

Colonic injury upregulates WISP-1 synthesis and secretion.

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Colonic injury upregulates WISP-1 synthesis and secretion. (A) WISP1 mRN...
(A) WISP1 mRNA levels were determined in tissue obtained from punch biopsies of intact colon (IT) and wounded colonic mucosa on post-injury days 1, 2, and 3 (***P < 0.001 and *P < 0.05, n = 3, mean ± SEM). (B) Laser confocal micrographs of frozen sections from intact colon and wounds on days 1 and 3 after wounding show WISP-1 expression (green), F-actin (red), and nuclei (blue). Scale bar: 100 μm. Original magnification ×20. (C) WISP1 mRNA levels in colon biopsies from healthy controls and IBD patients with active inflammation in the colon (***P < 0.001, n = 5, mean ± SEM). (D) Laser confocal micrographs of frozen sections from healthy and active IBD tissue show WISP-1 expression (green), F-actin (red), and nuclei (blue). Scale bar: 100 μm. UC, ulcerative colitis; CD, Crohn’s disease. (E) Lysates of healthy and active IBD tissue from human colon samples were immunoblotted to detect WISP-1, IL-10Rα, GBP-1, and GAPDH. B, D, and E show representative images from 3 experiments. Sample information pertaining to patient diagnosis, age, and treatment is provided in Supplemental Table 1. All statistical comparisons were performed using ANOVA with Tukey’s multiple comparisons post test.