Retinoic Acid Regulates S100 Proteins and Immune Responses in Viral Hepatitis

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The goal of this study is to understand how the liver microenvironment regulates antigen-presentation cell's egress to distant lymphoid organs in persistent viral hepatitis and how of innate lymphocytes modulate this process. The liver stores the body's majority of vitamin A, and is capable of producing large amounts of all- trans retinoic acid (RA), a principal vitamin A metabolite. Although RA is thought to induce T regulatory cells and mediate immune exhaustion in chronic viral hepatitis, the underlying molecular mechanisms of how RA shapes T cell priming in lymphoid organs are incompletely understood. Our preliminary data revealed unexpectedly that RA impedes dendritic cell (DC) functions by targeting novel S100A4, A6 and A10 proteins. These multifunctional proteins are involved in cell differentiation, the dynamics of cytoskeleton constituents, chemotaxis and cancer cell metastasis. Our data further suggest that the innate lymphocyte-derived IL-17/IL- 22 are involved in host defense and hepatoprotection and modulate T cell functions by stimulating RA production. Thus, our data have led to the hypothesis that RA is a crucial component of the liver microenvironment. It modulates DC functionality in the liver and is regulated by IL-22 secretion in the liver. Two specific aims will be pursued in this proposal: 1) Retinoic acid regulates antigen presentation by repressing S100 proteins. To test whether de novo RA biosynthesis indeed results in its immunoregulatory functions in the liver, we will feed mice a vitamin A-deficient diet and examine the effect of RA deprivation on DC and T cell functions, as well as on liver inflammation and viral persistence. To further examine the molecular mechanism of RA-mediated S100 protein regulation, we will treat bone marrow-derived DCs with LCMV and RA. We will analyze protein expression by mass spectrometry and pathway analysis. This study will reveal a critical molecular mechanism involving the role of hepatic RA in DC maturation and functions during viral infection. 2) To examine innate immunocyte-derived IL-17/IL-22 regulation in viral hepatitis. IL-17 and IL-22 belong to a group of cytokines typically secreted by Th17 cells, as well as innate immunocytes. In preliminary studies, we showed that intrahepatic IL-17 is critical for DC licensing and T cell priming, whereas IL-22 protects the liver in hepatitis. We will infect IL-22-/- and control mice with LCMV and examine their hepatic apoptosis and disease progression. To test the hypothesis that IL-17/IL-22 production in intrahepatic immunocytes is differentially regulated by several pathways, we will examine the effects of RORt, PI3K, mTOR and AhR through specific inhibitors. Our hypothesis addresses a knowledge gap regarding the effect of the liver cytokine environment on adaptive T cell responses and is potentially paradigm shifting. Our findings will have a significant impact on understanding hepatitis pathogenesis as well as future disease-modifying therapeutics.