Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by altered immune cell function in response to endotoxemia, but the mechanisms are not fully known or understood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formyl peptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterial functions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AH patients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatment ameliorates alcohol induced liver injury, inflammation, fibrosis, and endotoxemia while Fpr2-/- mice develop exacerbated liver injury, inflammation, fibrosis, and endotoxemia. Studies characterizing the RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but are warranted based on preliminary data.
Aim 1 :
This aim will determine if RvD1 acts solely through FPR2 to elicit protection in an animal of alcoholic liver disease (ALD).
Aim 2 :
Aim 2 a will determine if the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells.
Aim 2 b will establish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses against pathogenic threats.
Aim 3 : AH patient and healthy control acquired neutrophils and monocytes will be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic and phosphoproteomic analysis to measure receptor activation and to characterize the signaling pathway, respectively. Collectively this study will generate data that could identify RvD1 or FPR2 agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AH patient samples this study it is immediately impactful and informative for future treatment strategies. Novel biomarkers and therapeutic interventions are expected to come from the conclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway in neutrophils and monocytes is expected from this work as well.
Findings from this study will demonstrate whether enhanced RvD1-FPR2 signaling is a therapeutic option for alcoholic liver disease. These results will immediately impact the treatment strategies for alcoholic hepatitis patients who have high mortality rates under the current standard care. Advancements in the field of immunology and host-bacteria interactions, and the RvD1-FPR2 signaling pathway are expected from this work as well.
