Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function.
Shouval, Dror S. 1, 2, 23; Biswas, Amlan 1, 2, 23; Goettel, Jeremy A. 1, 2, 23; McCann, Katelyn 1, 23; Conaway, Evan 3; Redhu, Naresh S. 1, 2, 23; Mascanfroni, Ivan D. 4; Al Adham, Ziad 5; Lavoie, Sydney 1; Ibourk, Mouna 1; Nguyen, Deanna D. 6, 7; Samsom, Janneke N. 8, 23; Escher, Johanna C. 9, 23; Somech, Raz 10, 12, 23; Weiss, Batia 11, 12, 23; Beier, Rita 13, 23; Conklin, Laurie S. 14, 23; Ebens, Christen L. 15, 23; Santos, Fernanda G.M.S. 16, 23; Ferreira, Alexandre R. 16, 23; Sherlock, Mary 17, 23; Bhan, Atul K. 18, 19; Muller, Werner 20; Mora, Rodrigo J. 6, 7; Quintana, Francisco J. 4; Klein, Christoph 21, 23; Muise, Aleixo M. 5, 23; Horwitz, Bruce H. 2, 3, 23; Snapper, Scott B. 1, 7, 22, 23, *
[Article]
Immunity.
40(5):706-719, May 2014.
(Format: HTML, PDF)
SUMMARY: 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.
* IL-10R-deficient innate immune cells render WT CD4 T cells colitogenic
* Loss of innate IL-10R signaling impairs regulatory T cell generation and function
* IL-10R signaling regulates murine and human macrophage differentiation and function
(C) 2014Elsevier, Inc.
