Retinoic Acid Regulates S100 Proteins and Immune Responses in Viral Hepatitis

视黄酸调节病毒性肝炎中的 S100 蛋白和免疫反应

• 批准号: 9169284
• 负责人: JIAREN SUN
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169284
• 关键词: Address; Anabolism; Antigen Presentation; Antigens; Apoptosis; Bone Marrow; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Chemotaxis; Chronic Hepatitis; Chronic viral hepatitis; Clinical; Cues; Cytoskeleton; Data; Dendritic Cells; Development; Diet; Disease; Disease Progression; Distant; Environment; FRAP1 gene; Family; Flow Cytometry; Future; Gene Activation; Goals; Hepatic; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Host Defense; Immune; Immune response; Immunoassay; Immunosuppression; Inflammation; Interleukin-17; Knowledge; Label; Lead; Licensing; Liver; Liver Failure; Liver diseases; Lymphocyte; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Mediating; Molecular; Mus; Neoplasm Metastasis; Organ; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Peptides; Phosphorylation; Play; Prevention; Process; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Resolution; Role; S100 Proteins; Sampling; Shapes; Signal Pathway; Signal Transduction; Stream; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Tretinoin; Viral; Viral hepatitis; Virus Diseases; Vitamin A; Western Blotting; cancer cell; cytokine; deprivation; differential expression; exhaustion; feeding; genetic regulatory protein; inhibitor/antagonist; insight; interleukin-22; intrahepatic; liver inflammation; liver injury; lymph nodes; novel; protein expression

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.

本研究的目的是了解肝脏微环境是如何调节抗原呈递细胞的 持续性病毒性肝炎中向远处淋巴器官的转移以及先天性淋巴细胞如何调节这种转移 过程肝脏储存人体的大部分维生素A，并能够产生大量的所有- 反式维甲酸（RA）是维生素A的主要代谢产物。虽然RA被认为诱导T调节细胞 并介导慢性病毒性肝炎的免疫衰竭， 淋巴器官中T细胞启动的形状还不完全清楚。我们的初步数据显示 出乎意料的是，RA通过靶向新的S100 A4、A6和A10蛋白来阻碍树突状细胞（DC）功能。 这些多功能蛋白质参与细胞分化，细胞骨架成分的动力学， 趋化性和癌细胞转移。我们的数据进一步表明，先天性淋巴细胞来源的IL-17/IL-1 22个参与宿主防御和肝保护，并通过刺激RA调节T细胞功能 生产因此，我们的数据导致了这样的假设，即RA是肝脏的重要组成部分 微环境它调节肝脏中的DC功能，并受肝脏中IL-22分泌的调节。两 在该建议中将追求特定的目标：1）视黄酸通过抑制 S100蛋白。为了测试RA的从头生物合成是否确实导致了其在小鼠中的免疫调节功能， 肝脏，我们将喂养小鼠维生素A缺乏的饮食，并检查RA剥夺对DC和T细胞的影响 功能，以及肝脏炎症和病毒持久性。为了进一步研究分子机制 为了研究RA介导的S100蛋白调节，我们将用LCMV和RA处理骨髓来源的DC。我们将 通过质谱和途径分析来分析蛋白质表达。这项研究将揭示一个关键的 涉及肝RA在病毒感染期间DC成熟和功能中的作用的分子机制。（二） 目的探讨先天性免疫细胞源性IL-17/IL-22在病毒性肝炎中的调节作用。IL-17和IL-22属于A型 一组通常由Th 17细胞以及先天免疫细胞分泌的细胞因子。在初步研究中，我们 表明肝内IL-17对DC许可和T细胞启动至关重要，而IL-22在肝内保护肝脏。 肝炎我们将用LCMV感染IL-22-/-小鼠和对照小鼠，并检测它们的肝细胞凋亡和疾病 进展为了检验肝内免疫细胞中IL-17/IL-22的产生与肝内免疫细胞中IL-17/IL-22的产生有差异的假设， 通过几种途径的调节，我们将通过特异性的细胞内信号转导通路来检测ROR β t，PI 3 K，mTOR和AhR的作用。 抑制剂的我们的假设解决了关于肝脏细胞因子环境对肝细胞凋亡的影响的知识空白。 适应性T细胞反应和潜在的范式转变。我们的发现将对 了解肝炎发病机制以及未来的疾病修饰疗法。