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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Bibliographic Details
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
Format: Article
Language:English
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
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Summary: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.
ISSN:2470-9468
2470-9468
DOI:10.1126/sciimmunol.aau6571