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.