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IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response

Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-r...

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Published in:Science immunology 2019-06, Vol.4 (36)
Main Authors: Bernshtein, Biana, Curato, Caterina, Ioannou, Marianna, Thaiss, Christoph A, Gross-Vered, Mor, Kolesnikov, Masha, Wang, Qian, David, Eyal, Chappell-Maor, Louise, Harmelin, Alon, Elinav, Eran, Thakker, Paresh, Papayannopoulos, Venizelos, Jung, Steffen
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container_issue 36
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container_title Science immunology
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creator Bernshtein, Biana
Curato, Caterina
Ioannou, Marianna
Thaiss, Christoph A
Gross-Vered, Mor
Kolesnikov, Masha
Wang, Qian
David, Eyal
Chappell-Maor, Louise
Harmelin, Alon
Elinav, Eran
Thakker, Paresh
Papayannopoulos, Venizelos
Jung, Steffen
description Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency ( mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs.
doi_str_mv 10.1126/sciimmunol.aau6571
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Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency ( mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. 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subjects Animals
Colitis - immunology
Colitis - pathology
Epithelial Cells - immunology
Interleukin-22
Interleukin-23 - immunology
Interleukins - immunology
Intestines - immunology
Intestines - pathology
Macrophages - immunology
Male
Mice
Neutrophils - immunology
Receptors, Interleukin-10 - genetics
Receptors, Interleukin-10 - immunology
title IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response
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