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Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression
Author(s) -
Gandhirajan Anugraha,
Roychowdhury Sanjoy,
Kibler Christopher,
Bauer Seth R.,
Nagy Laura E.,
Vachharajani Vidula
Publication year - 2021
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14542
Subject(s) - sirtuin , immune system , sirtuin 1 , ethanol , chemistry , sepsis , microbiology and biotechnology , immunology , medicine , biology , biochemistry , downregulation and upregulation , enzyme , nad+ kinase , gene
Background Sepsis and septic shock kill over 270,000 patients per year in the United States. Sepsis transitions from a hyper‐inflammatory to a hypo‐inflammatory phase. Alcohol dependence is a risk factor for mortality from sepsis. Ethanol (EtOH) exposure impairs pathogen clearance through mechanisms that are not fully understood. Sirtuin 2 (SIRT2) interferes with pathogen clearance in immune cells but its role in the effects of EtOH on sepsis is unknown. We studied the effect of EtOH exposure on hyper‐ and hypo‐inflammation and the role of SIRT2 in mice. Methods We exposed C57Bl/6 (WT) mice to EtOH via drinking water and used intraperitoneal cecal slurry (CS)‐induced sepsis to study: (i) 7‐day survival, (ii) leukocyte adhesion (LA) in the mesenteric microcirculation during hyper‐ and hypo‐inflammation, (iii) peritoneal cavity bacterial clearance, and (iv) SIRT2 expression in peritoneal macrophages. Using EtOH‐exposed and lipopolysaccharide (LPS)‐stimulated RAW 264.7 (RAW) cell macrophages for 4 hours or 24 hours, we studied: (i) tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), and SIRT2 expression, and (ii) the effect of the SIRT2 inhibitor AK‐7 on inflammatory response at 24 hours. Lastly, we studied the effect of EtOH on sepsis in whole body Sirt2 knockout (SIRT2KO) mice during hyper‐ and hypo‐inflammation, bacterial clearance, and 7‐day survival. Results WT EtOH‐sepsis mice showed: (i) Decreased survival, (ii) Muted LA in the microcirculation, (iii) Lower plasma TNF‐α and IL‐6 expression, (iv) Decreased bacterial clearance, and (v) Increased SIRT2 expression in peritoneal macrophages versus vehicle‐sepsis. EtOH‐exposed LPS‐stimulated RAW cells showed: (i) Muted TNF‐α, IL‐6, and increased IL‐10 expression at 4 hours, (ii) endotoxin tolerance at 24 hours, and (iii) reversal of endotoxin tolerance with the SIRT2 inhibitor AK‐7. EtOH‐exposed SIRT2KO‐sepsis mice showed greater 7‐day survival, LA, and bacterial clearance than WT EtOH‐sepsis mice. Conclusion EtOH exposure decreases survival and reduces the inflammatory response to sepsis via increased SIRT2 expression. SIRT2 is a potential therapeutic target in EtOH with sepsis.