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A cytokine network involving IL-36?, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.

ABSTRACT: The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36? is a potent inducer of IL-23 both in vitro and in vivo. IL-36?-induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3-dependent (CD11b-CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-?B subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36?-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36? could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36?, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.

SUBMITTER: Ngo VL

PROVIDER: S-EPMC5984499 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.

Ngo Vu L VL Abo Hirohito H Maxim Estera E Harusato Akihito A Geem Duke D Medina-Contreras Oscar O Merlin Didier D Gewirtz Andrew T AT Nusrat Asma A Denning Timothy L TL

Proceedings of the National Academy of Sciences of the United States of America 20180514 22

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define ...[more]

PMID: 29760082

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Project description:BackgroundThe hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated.MethodsIntestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity.ResultsAfter alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3γ and α-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced Akkermansia, IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using in vitro cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3.ConclusionOur study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.

Dataset Information

A cytokine network involving IL-36?, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.

Publications

A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage.

Similar Datasets

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