乙醇暴露通过 Sirtuin 2 表达减轻脓毒症中的免疫反应。
Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression.
机构信息
Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
出版信息
Alcohol Clin Exp Res. 2021 Feb;45(2):338-350. doi: 10.1111/acer.14542. Epub 2021 Jan 23.
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.
背景
在美国，每年有超过 27 万名患者死于败血症和感染性休克。败血症从过度炎症反应阶段向低炎症反应阶段转变。酒精依赖是败血症死亡率的一个风险因素。乙醇（EtOH）暴露通过尚未完全了解的机制损害病原体清除。沉默调节蛋白 2（SIRT2）干扰免疫细胞中的病原体清除，但它在 EtOH 对败血症的影响中的作用尚不清楚。我们研究了 EtOH 暴露对超炎症和低炎症的影响，以及 SIRT2 在小鼠中的作用。
方法
我们通过饮用水使 C57Bl/6（WT）小鼠接触 EtOH，并使用腹腔盲肠浆液（CS）诱导的败血症来研究：（i）7 天存活率，（ii）超炎症和低炎症期间肠系膜微循环中的白细胞黏附（LA），（iii）腹腔内细菌清除率，以及（iv）腹腔巨噬细胞中的 SIRT2 表达。我们用 EtOH 暴露和脂多糖（LPS）刺激 RAW 264.7（RAW）细胞巨噬细胞 4 小时或 24 小时，研究了：（i）肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）和 SIRT2 表达，以及（ii）SIRT2 抑制剂 AK-7 在 24 小时时对炎症反应的影响。最后，我们研究了 EtOH 在全身 Sirt2 敲除（SIRT2KO）小鼠的超炎症和低炎症、细菌清除率和 7 天存活率中的作用。
结果
WT EtOH-败血症小鼠表现出：（i）存活率降低，（ii）微循环中的 LA 减弱，（iii）血浆 TNF-α和 IL-6 表达降低，（iv）细菌清除率降低，以及（v）与 vehicle-败血症相比，腹腔巨噬细胞中的 SIRT2 表达增加。EtOH 暴露的 LPS 刺激 RAW 细胞显示：（i）4 小时时 TNF-α、IL-6 和 IL-10 表达减弱，（ii）24 小时时内毒素耐受，以及（iii）SIRT2 抑制剂 AK-7 逆转内毒素耐受。EtOH 暴露的 SIRT2KO-败血症小鼠的 7 天存活率、LA 和细菌清除率均高于 WT EtOH-败血症小鼠。
结论
EtOH 暴露通过增加 SIRT2 表达降低败血症的存活率和炎症反应。SIRT2 是 EtOH 治疗败血症的潜在治疗靶点。
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