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

• Type of Material: Article
• Authors: Miguel Quiros, University of Michigan; Hikaru Nishio, Emory University; Philipp A Neumann, Technical University of Munich; Dorothee Siuda, University of Michigan; Jennifer Brazil, University of Michigan; Veronica Azcutia, University of Michigan; Roland Hilgarth, University of Michigan; Monique N. O'Leary, University of Michigan; Vicky Garcia Garcia-Hernandez, University of Michigan; Giovanna Leoni, Ludwig Maximilian University LMU Munich; Mingli Feng, University of Michigan; Gabriela Bernal, University of Michigan; Holly Williams, University of Michigan; Priya H. Dedhia, University of Michigan; Christian Gerner-Smidt, Emory University; Jason Spence, University of Michigan; Charles A. Parkos, University of Michigan; Timothy L. Denning, Georgia State University; Asma Nusrat, Emory University
• Language: English
• Date: 2017-09-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2018 American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI90229
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 127
• Issue: 9
• Start Page: 3516
• End Page: 3526
• Grant/Funding Information: This work was supported by NIH grants (RO1DK055679, RO1DK089763, and DK059888, to AN; R01DK097256, to TLD; and DK61739, DK72564, and DK79392, to CAP); a Crohn’s and Colitis Foundation of America Research Fellowship Award (326912, to MQ); and the German Research Foundation (DFG) (NE 1834/1-1, to PAN).
• Keywords: DENDRITIC CELLS; WOUND REPAIR; IFN-GAMMA; Medicine, Research & Experimental; Research & Experimental Medicine; Life Sciences & Biomedicine; T-CELL RESPONSES; CREB; Science & Technology; MICE; PROLIFERATION; INTERLEUKIN-10; CYTOKINE IL-10; INFLAMMATORY-BOWEL-DISEASE
• Research Categories: Health Sciences, Pathology

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.