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Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis.

ABSTRACT: Although large amounts of vitamin A and its metabolite all-trans retinoic acid (RA) are stored in the liver, how RA regulates liver immune responses during viral infection remains unclear. In this study, we demonstrated that IL-22, mainly produced by hepatic ?? T cells, attenuated liver injury in adenovirus-infected mice. RA can promote ?? T cells to produce mTORC1-dependent IL-22 in the liver, but inhibits IFN-? and IL-17. RA also affected the aptitude of T cell responses by modulating dendritic cell (DC) migration and costimulatory molecule expression. These results suggested that RA plays an immunomodulatory role in viral infection. Proteomics data revealed that RA downregulated S100 family protein expression in DCs, as well as NF-?B/ERK pathway activation in these cells. Furthermore, adoptive transfer of S100A4-repressed, virus-pulsed DCs into the hind foot of naive mice failed to prime T cell responses in draining lymph nodes. Our study has demonstrated a crucial role for RA in promoting IL-22 production and tempering DC function through downregulating S100 family proteins during viral hepatitis.

SUBMITTER: Jie Z

PROVIDER: S-EPMC5436614 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis.

Jie Zuliang Z Liang Yuejin Y Yi Panpan P Tang Hui H Soong Lynn L Cong Yingzi Y Zhang Kangling K Sun Jiaren J

Journal of immunology (Baltimore, Md. : 1950) 20170331 9

Although large amounts of vitamin A and its metabolite all-<i>trans</i> retinoic acid (RA) are stored in the liver, how RA regulates liver immune responses during viral infection remains unclear. In this study, we demonstrated that IL-22, mainly produced by hepatic γδ T cells, attenuated liver injury in adenovirus-infected mice. RA can promote γδ T cells to produce mTORC1-dependent IL-22 in the liver, but inhibits IFN-γ and IL-17. RA also affected the aptitude of T cell responses by modulating d ...[more]

PMID: 28363907

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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

Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis.

Publications

Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis.

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