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Immunity. 2014 May 15;40(5):706-19. doi: 10.1016/j.immuni.2014.03.011. Epub 2014 May 1.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
2
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
3
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
4
Center of Neurological Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
6
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
7
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
8
Laboratory of Pediatric Gastroenterology, Erasmus Medical Center-Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
9
Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
10
Pediatric Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52661, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
11
Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52661, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
12
Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
13
Department of Gastroenterology, Children's National Medical Center, Washington, D.C. 20010, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
14
Division of Pediatric Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
15
Hospital das Clínicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 30130-100, Brazil; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
16
Division of Gastroenterology, McMaster Children's Hospital, West Hamilton, Ontario L8N 3Z5, Canada; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
17
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
18
Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
19
Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
20
Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
21
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
22
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS). Electronic address: ssnapper@hms.harvard.edu.

Abstract

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

PMID:
24792912
PMCID:
PMC4513358
DOI:
10.1016/j.immuni.2014.03.011
[Indexed for MEDLINE]
Free PMC Article
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