1. Immunology and Inflammation
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Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

  1. Naresh S Redhu
  2. Vasudevan Bakthavatchalu
  3. Evan A Conaway
  4. Dror S Shouval
  5. Amy M Tsou
  6. Jeremy A Goettel
  7. Amlan Biswas
  8. Chuanwu Wang
  9. Michael Field
  10. Werner Muller
  11. Andre Bleich
  12. Ning Li
  13. Georg K Gerber
  14. Lynn Bry
  15. James G Fox
  16. Scott B Snapper  Is a corresponding author
  17. Bruce H Horwitz  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Massachusetts Institute of Technology, United States
  3. Brigham and Women's Hospital, United States
  4. University of Manchester, United Kingdom
  5. Hannover Medical School, Germany
  6. Harvard Medical School, United States
Research Article
  • Cited 13
  • Views 2,310
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Cite this article as: eLife 2017;6:e27652 doi: 10.7554/eLife.27652

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.

Article and author information

Author details

  1. Naresh S Redhu

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Vasudevan Bakthavatchalu

    Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Evan A Conaway

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dror S Shouval

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amy M Tsou

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jeremy A Goettel

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Amlan Biswas

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4299-1001
  8. Chuanwu Wang

    Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael Field

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Werner Muller

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Andre Bleich

    Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Ning Li

    Massachusetts Host-Microbiome Center, Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Georg K Gerber

    Massachusetts Host-Microbiome Center, Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9149-5509
  14. Lynn Bry

    Massachusetts Host-Microbiome Center, Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. James G Fox

    Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Scott B Snapper

    Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    For correspondence
    Scott.Snapper@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  17. Bruce H Horwitz

    Harvard Medical School, Boston, United States
    For correspondence
    bhorwitz@partners.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8123-8728

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).

Reviewing Editor

  1. Andrew J MacPherson, University of Bern, Switzerland

Publication history

  1. Received: April 11, 2017
  2. Accepted: July 1, 2017
  3. Accepted Manuscript published: July 5, 2017 (version 1)
  4. Accepted Manuscript updated: July 7, 2017 (version 2)
  5. Version of Record published: July 27, 2017 (version 3)

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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