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Intestinal Mucosa Pro‐Repair Properties of Macrophage Derived IL‐10 are Mediated by CREB Triggered Epithelial WISP‐1 Signaling
Author(s) -
Quiros Miguel,
Nishio Hikaru,
Neumann Philipp A,
Leoni Giovanna,
GarciaHernandez Vicky,
Siuda Dorothee,
Feng Mingli,
Bernal Gabriela,
Hilgarth Roland,
Williams Holly,
Brazil Jennifer C,
Dedhia Priya H,
Spence Jason,
Parkos Charles A,
Denning Timothy L,
Nusrat Asma
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.465.2
Subject(s) - wound healing , microbiology and biotechnology , creb , immune system , interleukin 22 , immunology , cd11c , biology , intestinal mucosa , macrophage , intestinal epithelium , innate immune system , cancer research , epithelium , medicine , cytokine , interleukin , in vitro , transcription factor , phenotype , biochemistry , genetics , gene
In response to injury, epithelial cells migrate and proliferate to cover denuded mucosal surfaces and repair the barrier defect. This process is orchestrated by a dynamic cross‐talk between immune cells and the epithelium. However, the underlying mechanisms of repair remain incompletely understood. Here, we report that increased generation of IL‐10 in healing wounds orchestrates repair of the intestinal mucosal barrier. Conditional deletion of IL‐10 specifically in CD11c‐expressing cells in‐vivo identified macrophages as a critical innate immune contributor to IL‐10‐mediated mucosal wound repair. Consistent with these findings, wound closure in Rag1 KO mice was unimpaired, suggesting that adaptive immune cells do not influence intestinal mucosal wound repair. Furthermore, 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 promoted epithelial proliferation and wound closure by activation of epithelial beta catenin and cyclin D1. These findings identify an important role of macrophages derived IL‐10 that cross‐talks with epithelial WISP‐1 signaling to orchestrate mucosal repair. Support or Funding Information This work was supported by NIH grants (RO1DK055679, RO1DK089763 to A. Nusrat; R01DK097256 to T. Denning; and DK61739, DK72564 and DK79392 to C.A. Parkos); the Crohn's and Colitis Foundation of America Research Fellowship Award (326912) to M. Quiros