Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor
- Boston Children's Hospital, United States
- Massachusetts Institute of Technology, United States
- Brigham and Women's Hospital, United States
- University of Manchester, United Kingdom
- Hannover Medical School, Germany
- Harvard Medical School, United States
Abstract
Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first 2 weeks of life, intestinal inflammation and macrophage dysfunction begin during the 3rd week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.
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Funding
Crohn's and Colitis Foundation of America (RFA381023)
- Naresh S Redhu
Canadian Institutes of Health Research (201411MFE-339308-254788)
- Naresh S Redhu
National Institutes of Health (T32-OD010978-26)
- James G Fox
Leona M. and Harry B. Helmsley Charitable Trust
- Scott B Snapper
Wolpow Family Chair in IBD Research and Treatment
- Scott B Snapper
National Institutes of Health (R01-OD011141)
- James G Fox
National Institutes of Health (P30-ES002109)
- James G Fox
National Institutes of Health (R01-AI00114)
- Bruce H Horwitz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted following approval from the Animal Resources at Children's Hospital, per regulations of the Institutional Animal Care and Use Committees (IACUC assurance number A3303-01).
Copyright
© 2017, Redhu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor
eLife 6:e27652.
https://doi.org/10.7554/eLife.27652
