IL17 dependent angiocrine signaling drives inflammation in alcohol associated hepatitis
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Principal Investigator: Mengfei Liu Organization: YALE UNIVERSITY Fiscal Year: 2024 Award: $75,600 Funding agency: National Institute on Alcohol Abuse and Alcoholism 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 stimulates CXCL chemokine production with TNFα, but the underlying mechanism is not clear. The regulation of IL17 production from T cells also requires further study. 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. This supplement will provide additional support for personnel hiring and training to further the work proposed in Aim 1 during my upcoming leave of absence. In Aim 1, we explored the role of IκB𝜁𝜁, a transcription factor previously implicated in IL17 signaling, in mediating the interaction between IL17 and TNFα signaling pathways. We are planning to generate LSEC-specific IκB𝜁𝜁 KO mice and test the effect of IκB𝜁𝜁 deletion in AH model. In addition, we will use an anti-IL17 antibody to observe the effect of IL17 axis inhibition in AH model. We plan to isolate LSECs from control and treated mice and submit these samples for bulk RNA-sequencing analysis. Better understanding of the IL17 mediated angiocrine signaling process 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. Terms: <(TNF)-α><3C-based approach><3C-based assay><3C-based method><3C-based strategy><3C-based technique><3C-based technology><4C-seq><Affect><Alcohol associated hepatitis><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcoholic Hepatitis><Alcoholic Liver Diseases><Antibodies><Antimorphic mutation><Assay><Autoimmune><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological><Biological Assay><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><CRISPR><CRISPR/Cas system><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><CXCL1><CXCL1 gene><Cachectin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><ChIP assay><Chemotactic Cytokines><Chromatin Conformation Capture and Sequencing><Clustered Regularly Interspaced Short Palindromic Repeats><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><DNA><Data><Deoxyribonucleic Acid><Development><Discontinuous Capillary><Disease><Disorder><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Endothelial Cells><Endothelium><Enhancers><Ethanol-induced hepatitis><Family><GRO1><GROA><General Transcription Factor Gene><General Transcription Factors><Genes><Guide RNA><Heavy Drinking><Hepatic Parenchyma><Homologous Chemotactic Cytokines><Human Resources><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune Cell Activation><Immune infiltrates><Immunes><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Injury to Liver><Intercrines><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin Suppression><Interleukin-17><Intracellular Communication and Signaling><Isoforms><KO mice><Knock-in><Knock-out Mice><Knockout Mice><Knowledge><L-Threonine><Ligands><Liver><Liver parenchyma><MGSA><Macrophage-Derived TNF><Manpower><Marrow Neutrophil><Mediating><Mice><Mice Mammals><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Mission><Modeling><Molecular Target><Monocyte-Derived TNF><Murine><Mus><NIAAA><National Institute on Alcohol Abuse and Alcoholism><Network Analysis><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Nuclear><Null Mouse><Paracrine Communication><Paracrine Signaling><Pathogenesis><Pathway Analysis><Pathway interactions><Patients><Phosphorylation><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Process><Production><Protein Isoforms><Protein Phosphorylation><RNA Seq><RNA sequencing><RNAseq><Regulation><Regulatory Element><Role><SCYB1><SIS cytokines><Sampling><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sinusoid><Sinusoidal Capillary><Small Interfering RNA><Source><System><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Threonine><Tissues><Training><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Up-Regulation><Upregulation><Variant><Variation><Work><alcohol abuse therapy><alcohol abuse treatment><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol treatment><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><biologic><biological signal transduction><chemoattractant cytokine><chemokine><chromatin conformation capture><chromatin immunoprecipitation><chromosome capture><chromosome conformation capture><cytokine><developmental><drink heavily><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><experiment><experimental research><experimental study><experiments><extreme drinking><gRNA><gene network><heavy alcohol use><hepatic body system><hepatic damage><hepatic inflammation><hepatic injury><hepatic organ system><immune activation><immune cell infiltrate><in vivo><inflamed liver><inhibitor><knockin><liver damage><liver inflammation><liver injury><member><microfluidic chip><migration><neutrophil><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><paracrine><pathway><personnel><pharmacologic><promoter><promotor><response><siRNA><social role><synergism><therapeutic target><thymus derived lymphocyte><transcription factor><transcriptome sequencing><transcriptomic sequencing><transcriptomics>