Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis

Immunity. 2014 May 15;40(5):720-33. doi: 10.1016/j.immuni.2014.03.012. Epub 2014 May 1.

Abstract

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-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-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 CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cells, Cultured
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / immunology*
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Chemokine / biosynthesis
  • Receptors, Interleukin-10 / genetics
  • Receptors, Interleukin-10 / immunology*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • IL10 protein, mouse
  • Receptors, Chemokine
  • Receptors, Interleukin-10
  • Interleukin-10

Associated data

  • GEO/GSE56444