Immuno-metabolic dysfunction in alcohol with sepsis

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Abstract Alcohol dependence is an independent risk factor for sepsis-mortality but the mechanisms are unknown. The goal of this proposal is to fill this gap and investigate potential targeted treatment. Ethanol represses immune response and increases mortality in mouse model of sepsis. Sepsis kills over 250,000 patients annually and is the most expensive condition in the US. Immune response in sepsis transitions from early/ hyper-inflammatory- to a late/hypo-inflammatory and immunosuppressive phase; majority of the sepsis-mortality occurs during hypo-inflammation with inability to clear pathogen. Leukocyte adhesion prior to extravasation and pathogen clearance, is a rate determining factor in inflammation. Using in vivo leukocyte adhesion to test microvascular inflammatory response in mice and cell models, we reported, sirtuins (SIRTs), the known anti-inflammatory proteins, are crucial for transition to hypo-inflammation. Specifically, we reported a crucial role for sirtuin 2 (SIRT2) in sepsis. SIRT2 expression is decreased during hyper- and induced during hypo-inflammation in obese- sepsis mice. Our strong preliminary data suggests that ethanol induces early and sustained SIRT2 expression, represses microvascular leukocyte adhesion in vivo, impairs bacterial clearance and decreases survival in sepsis- mice. In contrast, ethanol with sepsis in SIRT2 deficient mice show significantly improved leukocyte adhesion response, bacterial clearance and increased survival. We identified SIRT2 coupling with p38 MAPK activation and IL-10 expression in ethanol with sepsis. We also found, mitochondrial accumulation of SIRT2 was accompanied by impaired mitochondrial function and glycolysis. Our overarching goal is to study immuno- metabolic dysfunction in ethanol with sepsis. We will study the hypothesis that ethanol causes immuno- metabolic dysfunction in sepsis via SIRT2-p38 MAPK- IL-10 pathway, in two complimentary but independent specific aims: Aim 1: To determine the effect of ethanol on immuno-metabolic function in sepsis. Aim 2: To determine the role of SIRT2 in immuno-metabolic dysfunction in ethanol with sepsis. Successful completion of these experiments will inform the role of SIRT2 in immuno-metabolic dysfunction with alcohol drinking and potentially lead to new SIRT2-based therapeutic targets with wide-ranging applications to treat acute/chronic inflammatory conditions.