Research ArticleINFLAMMATION

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

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Science Immunology  14 Jun 2019:
Vol. 4, Issue 36, eaau6571
DOI: 10.1126/sciimmunol.aau6571

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A Colitis Circuit

Cytokines are known to play a critical role in maintaining gut homeostasis, but their specific cellular sources are less well understood. Here, Bernshtein et al. used a murine model of inflammatory bowel disease (IBD) in which macrophages specifically lack expression of interleukin-10 receptor (IL-10R), and mice developed symptoms of spontaneous colitis similar to that observed in children with IL-10R mutations. They identified macrophage-derived IL-23 as the cytokine critical to induce the pathology. IL-23 triggered accumulation and IL-22 production by TH17 cells that, in turn, promoted production of chemokines by colonic epithelial cells and destructive neutrophil recruitment. Together, these results reveal the mechanism by which intestinal IL-10R–deficient macrophages drive IBD pathogenesis.

Abstract

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 (Cx3cr1Cre:Il10rafl/fl 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 Cx3cr1Cre:Il10rafl/fl:Il23afl/fl 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.

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