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IL17 dependent angiocrine signaling drives inflammation in alcohol associated hepatitis

IL17 依赖性血管分泌信号传导驱动酒精相关性肝炎的炎症

基本信息

批准号：
10837927
负责人：
Mengfei Liu
金额：
$ 19.06万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10837927
关键词：
Affect Alcoholic Hepatitis Alcoholic Liver Diseases Autoimmune Biological Biological Assay Blood Vessels CXCL1 gene Cells Chemotaxis Chromatin Conformation Capture and Sequencing Circulation Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Data Development Discontinuous Capillary Disease Dominant-Negative Mutation Endothelial Cells Endothelium Enhancers Family Gene Expression Genes Genome Guide RNA Heavy Drinking Hereditary Disease IL17 gene Immune Infiltration Inflammation Inflammatory Inflammatory Response Interleukin Suppression Knock-in Knock-in Mouse Knockout Mice Knowledge Ligands Liver Liver parenchyma Mediating Microfluidic Microchips Mission Modeling Molecular Target Mus National Institute on Alcohol Abuse and Alcoholism Neutrophil Infiltration Nuclear Paracrine Communication Pathogenesis Pathway Analysis Pathway interactions Patients Phosphorylation Process Production Protein Isoforms Regulation Regulator Genes Regulatory Element Role Signal Pathway Signal Transduction Small Interfering RNA Source System T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing Threonine Tissues Transcriptional Regulation Transgenic Mice Up-Regulation Variant Viral Work alcohol abuse therapy chemokine chromatin immunoprecipitation chromosome conformation capture cytokine experimental study gene network immune activation immune cell infiltrate in vivo inhibitor liver inflammation liver injury member migration mouse model neutrophil new therapeutic target novel novel therapeutics paracrine pharmacologic promoter response synergism targeted treatment therapeutic target transcription factor transcriptome sequencing transcriptomics

项目摘要

Project Abstract Alcoholic hepatitis (AH) is characterized by intense liver inflammation and injury in the setting of excess alcohol ingestion. Cytokine and chemokine upregulation leads to immune cell infiltration and drives inflammation in AH. Liver sinusoidal endothelial cells (LSEC) are an important source of chemokine expression in the liver and participate in paracrine signaling to attract immune cells in a process termed “angiocrine signaling”. Pathway analysis of AH liver RNA-sequencing suggests a potential role of IL17 in mediating LSEC angiocrine signaling. IL17 is a cytokine involved in many autoimmune and inflammatory disorders. Our preliminary data shows that IL17 synergically stimulate CXCL chemokine production with TNF, but the underlying mechanism is not clear. The regulation of IL17 production from T cells also requires further study. Super enhancers are DNA regulatory elements that complex with target gene promoters to drive gene expression. Our previous work has highlighted the role of super enhancers in AH inflammation response. Here, we hypothesize that LSECs increase inflammatory chemokine expression and enhance immune cell transmigration into the liver parenchyma in response to T cell IL17 upregulation by super enhancer activation. To test our hypothesis, we will employ complementary cell biologic and in vivo approaches to study the following specific aims: Aim 1. LSECs enhance CXCL1-dependent neutrophil transendothelial migration in response to IL17; Aim 2. Therapeutic targeting of a super enhancer in T cells downregulates IL17 and ameliorates inflammation in AH. In Aim 1, we will explore the role of IκB𝜁, a transcription factor previously implicated in IL17 signaling, in mediating the interaction between IL17 and TNF signaling pathways. We will also assess the transcriptomic changes of IL17 and TNF stimulation and IκB𝜁 silencing on LSECs by RNA-sequencing. Using microfluidic devices to simulate liver microvascular circulation, we will directly observe the effects of IL17/TNF stimulation and IκB𝜁 inhibition on neutrophil chemotaxis. In Aim 2, we will identify the IL17 super enhancer by chromosome conformation capture assays. We will assess the feasibility of CRISPR-mediated sequence-specific suppression of the IL17 super enhancer. We will use a Cre dependent dCas9-KRAB knockin mice with AAV6 viral delivery of single guide RNA to target the IL17 super enhancer in vivo. We aim to achieve T cell-specific suppression of IL17 expression and assess its effect on AH inflammatory response in a murine model. Indeed, in vivo CRISPR gene-editing has already been applied clinically to treat hereditary disorders, highlighting the translational promise of precision genome-targeting therapies. Better understanding of the IL17 mediated angiocrine signaling process and IL17 super enhancer regulation may reveal novel therapeutic targets for treatment of AH. Therefore, our overall aims and approaches are aligned with the mission of NIAAA to further understanding and treatment of alcohol- associated liver diseases.

项目摘要