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

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

Funding

FundersFunder number
Helmsley Foundation
Lord Alliance Weizmann Manchester Life Science Programme
Seventh Framework Programme305564
United States-Israel Binational Science Foundation

    Fingerprint

    Dive into the research topics of 'Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis'. Together they form a unique fingerprint.

    Cite this