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 6

WISP-1 promotes intestinal epithelial wound healing.

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WISP-1 promotes intestinal epithelial wound healing. (A) Intestinal epit...
(A) Intestinal epithelial wound closure percentage was calculated by measuring wound widths 0, 12, and 24 hours after wounding (***P < 0.001, n = 4, mean ± SEM). Cells were incubated with WISP-1 (500 nM) in the presence of WISP-1–inhibitory Abs (α–WISP-1) (10 μg/wound) and IgG-matched control Abs. (B) Percentage of wound closure in cells after siRNA-mediated downregulation of WISP-1 (WISP-1 siRNA) or scramble control siRNA (*P < 0.05 and **P < 0.01; n = 8, mean ± SEM) and treatment with rhIL-10 (100 nM), WISP-1 (500 nM), or BSA. (C and D) Epithelial cell proliferation was determined by analysis of EdU incorporation in control epithelial cells, cells with siRNA-mediated downregulation of WISP-1 (WISP-1 siRNA), WISP-1–inhibitory Abs with corresponding IgG-matched control (10 μg/well). (C, ***P < 0.001, n = 4, mean ± SEM), and in cells treated with rhIL-10 (100 nM), WISP-1 (500 nM), or BSA (D, *P < 0.05 and ***P < 0.001, n = 4, mean ± SEM). (E) POU5F1 and NANOG qPCR of SKCO-15 cells treated with WISP-1 (500 nM) or BSA (**P < 0.01; n = 3, mean ± SEM). (F) Intestinal epithelial cells from scratch-wounded monolayers were treated with BSA, IL-10 (100 nM), or WISP-1 (500 nM) for 2 hours. Harvested cells were immunoblotted for the pro-proliferative protein c-myc and the loading control GAPDH. Blot is representative of 3 experiments. (G) Endoscopic images of healing mucosal wounds 1 and 3 days after biopsy-induced injury in WT mice that were administered WISP-1–neutralizing Ab or an IgG isotype control into the wound bed (***P < 0.001, n = 5, mean ± SEM). All statistical comparisons were performed using ANOVA with Tukey’s multiple comparisons post test and a 2-tailed Student’s t test.