Journal
IMMUNITY
Volume 40, Issue 5, Pages 720-733Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2014.03.012
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Funding
- BSF
- Helmsley Foundation
- Lord Alliance Weizmann Manchester Life Science Programme
- European Community [305564]
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Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10R alpha) mutations in intestinal lamina propria-resident chemokine receptor CX(3)CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX(3)CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.
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