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IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis

Zindl, Carlene L. and Lai, Jen-Feng and Lee, Yun Kyung and Maynard, Craig L. and Harbour, Stacey N. and Ouyang, Wenjun and Chaplin, David D. and Weaver, Casey T. (2013) IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proceedings of the National Academy of Sciences of the United States of America, 110 (31). pp. 12768-12773. ISSN 0027-8424. PMCID PMC3732935. doi:10.1073/pnas.1300318110.

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IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23–dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNF-α. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22–competent neutrophils to Il22a-deficient mice protected the colonic epithelium from dextran sodium sulfate-induced damage. In addition, IL-22–producing neutrophils targeted colonic epithelial cells to up-regulate the antimicrobial peptides, RegIIIβ and S100A8. This study establishes a role for neutrophils in providing IL-22–dependent mucosal epithelial support that contributes to the resolution of colitis.

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Additional Information:© 2013 National Academy of Sciences. Edited by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved May 22, 2013 (received for review January 10, 2013). Published online before print June 18, 2013. We thank Andrei Kruglov (The Trudeau Institute) for critical technical advice; T. Schoeb and the Comparative Pathology Laboratory for histology scoring; B. Clodfelder-Miller and the Cellular and Molecular Neuropathology Core at the University of Alabama at Birmingham (UAB) for laser-capture microdissection; M. Spell at the Center for Aids Research Flow Cytometry Core at UAB for sorting; M. Chimento at the High Resolution Imaging Facility at UAB for transmission electron microscopy; D. O’Quinn, J. Oliver, B. J. Parsons, and M. Zeng for expert technical assistance; and G. Gaskins for editorial assistance. This work was supported by grants from the National Institutes of Health (NIH) and the Crohn’s and Colitis Foundation (to C.T.W.) and by T32 Training Grant funds from NIH/National Institute of Allergy and Infectious Diseases and the UAB Training Program in Immunologic Diseases and Basic Immunology (to C.L.Z.). Author contributions: C.L.Z., D.D.C., and C.T.W. designed research; C.L.Z., J.-F.L., Y.K.L., C.L.M., and S.N.H. performed research; W.O. contributed new reagents/analytic tools; C.L.Z., J.-F.L., Y.K.L., C.L.M., S.N.H., D.D.C., and C.T.W. analyzed data; and C.L.Z. and C.T.W. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission.
Funding AgencyGrant Number
Crohn’s and Colitis FoundationUNSPECIFIED
NIH/National Institute of Allergy and Infectious Diseases T32 Training GrantUNSPECIFIED
Immunologic Diseases and Basic Immunology UAB Training ProgramUNSPECIFIED
Subject Keywords:interleukin-22; intestinal inflammation; leukocytes
Issue or Number:31
PubMed Central ID:PMC3732935
Record Number:CaltechAUTHORS:20130906-154109904
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41155
Deposited By: Tony Diaz
Deposited On:16 Sep 2013 21:58
Last Modified:10 Nov 2021 04:26

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