Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function Academic Article uri icon

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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.

authors

  • Shouval, Dror S
  • Biswas, Amlan
  • Goettel, Jeremy A
  • McCann, Katelyn
  • Conaway, Evan
  • Redhu, Naresh S
  • Mascanfroni, Ivan D
  • Al Adham, Ziad
  • Lavoie, Sydney
  • Ibourk, Mouna
  • Nguyen, Deanna D
  • Samsom, Janneke N
  • Escher, Johanna C
  • Somech, Raz
  • Weiss, Batia
  • Beier, Rita
  • Conklin, Laurie S
  • Ebens, Christen L
  • Santos, Fernanda GMS
  • Ferreira, Alexandre R
  • Sherlock, Mary
  • Bhan, Atul K
  • Müller, Werner
  • Mora, J Rodrigo
  • Quintana, Francisco J
  • Klein, Christoph
  • Muise, Aleixo M
  • Horwitz, Bruce H
  • Snapper, Scott B

publication date

  • May 2014

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