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 CX3CR1hi macrophages as a decisive factor that determines gut health or inflammation.
| Original language | English |
|---|---|
| Pages (from-to) | 720-733 |
| Number of pages | 14 |
| Journal | Immunity |
| Volume | 40 |
| Issue number | 5 |
| DOIs | |
| State | Published - 15 May 2014 |
| Externally published | Yes |
Bibliographical note
Funding Information:We would like to thank all members of the Jung laboratory for discussion, the staff members of the Weizmann sorting facility for technical support, and Ron Rotkopf for advice concerning statistics. This work was supported by the BSF, the Helmsley Foundation, and a research grant from the Lord Alliance Weizmann Manchester Life Science Programme (to S.J. and W.M). S.J. was a Helmsley Scholar at the Crohn’s & Colitis Foundation. C.R.W. and W.M received funding from the European Community’s Seventh Framework Programme (FP7/2012-2017) under grant agreement n° 305564 (SysmedIBD).