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

Ehud Zigmond, Biana Bernshtein, Gilgi Friedlander, Catherine R. Walker, Simon Yona, Ki Wook Kim, Ori Brenner, Rita Krauthgamer, Chen Varol, Werner Müller, Steffen Jung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

426 Scopus citations

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 languageAmerican English
Pages (from-to)720-733
Number of pages14
JournalImmunity
Volume40
Issue number5
DOIs
StatePublished - 15 May 2014
Externally publishedYes

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).

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