title: Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis.
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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; The Research Center for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Zigmond
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Biana
authors.initials: B
authors.lastname: Bernshtein
authors.affiliation: Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gilgi
authors.initials: G
authors.lastname: Friedlander
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Walker
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Yona
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Brenner
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Rita
authors.initials: R
authors.lastname: Krauthgamer
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: s.jung@weizmann.ac.il.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000096:biosynthesis; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C556062:IL10 protein, mouse; D019707:Receptors, Chemokine; D053701:Receptors, Interleukin-10; D016753:Interleukin-10