Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Abstract

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.

A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis

“…influenzae , or E . coli ) as a challenge [ 32 , 36 , 40 – 42 , 65 , 79 , 86 ]; six used CLP model [ 36 , 38 , 39 , 76 , 78 , 82 ]; one used cecal slurry injection [ 83 ]; three studies used experimental colitis model [ 67 , 68 , 84 ]; one animal study used lipoteichoic acid [ 61 ]; one used 10–40 μg/mouse CpG DNA (TLR9 agonist) [ 63 ]; two used 500 nmole 1V136 or 20–100 μg R848 (TLR7 agonists), 25 μg/mouse Pam3CSK4 (TLR2 agonist), or 25 μg/mouse pIC (TLR3 agonist) [ 62 , 81 ].…”

“…All included human studies (12 studies) used LPS administration with in vivo doses of 2-4 ng/kg. Most animal studies (16 studies) used LPS administration with in vivo doses of 0.1-45 mg/kg in mouse or 2-400 μg/mouse via injection or 100 μg/mL via inhalation in mouse or 10 mg/lamb/injection, and with ex vivo doses of 1-1000 μg/mL; eight used treatments with bacteria (6000-10 7 colony-forming units (CFUs) of N. meningitidis, K. pneumoniae, S. pneumoniae, H. influenzae, or E. coli) as a challenge [32, 36, 40-42, 65, 79, 86]; six used CLP model [36,38,39,76,78,82]; one used cecal slurry injection [83]; three studies used experimental colitis model [67,68,84]; one animal study used lipoteichoic acid [61]; one used 10-40 μg/mouse CpG DNA (TLR9…”

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

“…The role of SIRT2 in the immune response beyond cancer is also an interesting question. In general, SIRT2 has been shown to suppress the immune reaction in a variety of illnesses including sepsis 51 , chronic staphylococcal infection 52 , and tuberculosis 53 . Ethanol exposure increased SIRT2 expression and reduced the inflammatory response to sepsis.…”

Ethanol Consumption and Sepsis: Mechanisms of Organ Damage

“…Sepsis may increase the levels of IL-6 and TNF-α [4,15], damaging different organs [5,26] culminating in septic shock [22]. Increased levels of blood urea nitrogen and creatinine may occur during sepsis, important markers of kidney damage [4].…”

“…Ethanol consumption directly affects immune function, leading to a decrease in the lymphocytic response, as well as alteration in cytokine production by lymphocytes and macrophages [15]. Other studies have demonstrated that the administration of ethanol suppresses the elimination of bacteria present in sepsis, with decreased pro-inflammatory chemokine levels (TNF-α and IL-6) [1,4,26]. The decrease in TNF-α itself may be responsible for the decreased recruitment of neutrophils, resulting in a less robust immune response [4].…”