Sirtuin 1 缺失增加脓毒症中的炎症和死亡率。
Sirtuin 1 deletion increases inflammation and mortality in sepsis.
机构信息
From the Division of Trauma, Critical Care, and Burn (H.E.L., K.M.S., C.A.S.), Ohio State University Wexner Medical Center, Ohio State University, Columbus, Ohio; and Institute for Diabetes, Obesity and Metabolism (J.A.B.), and Department of Physiology (J.A.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
出版信息
J Trauma Acute Care Surg. 2022 Nov 1;93(5):672-678. doi: 10.1097/TA.0000000000003751. Epub 2022 Jul 19.
BACKGROUND
Sepsis is a hyperinflammatory response to infection that can lead to multiorgan failure and eventually death. Often, the onset of multiorgan failure is heralded by renal dysfunction. Sirtuin 1 (SIRT1) promotes cellular stress resilience by inhibiting inflammation and promoting mitochondrial function. We hypothesize that SIRT1 plays an important role in limiting the inflammatory responses that drive organ failure in sepsis, predominantly via expression in myeloid cells.
METHODS
We performed cecal ligation and puncture (CLP) on whole body SIRT1 knockout (S1KO) and myeloid cell-specific S1KO (S1KO-LysMCre) mice on a C57BL/6J background. Serum interleukin (IL)-6 was quantified by enzyme-linked immunosorbent assay. Renal mitochondrial complex activity was measured using Oxygraph-2k (Oroboros Instruments, Innsbruck, Austria). Blood urea nitrogen (BUN) was measured from serum. Survival was monitored for up to 5 days.
RESULTS
Following CLP, S1KO mice had decreased renal mitochondrial complex I-dependent respiratory capacity (241.7 vs. 418.3 mmolO2/mg/min, p = 0.018) and renal mitochondrial complex II-dependent respiratory capacity (932.3 vs. 1,178.4, p = 0.027), as well as reduced rates of fatty acid oxidation (187.3 vs. 250.3, p = 0.022). Sirtuin 1 knockout mice also had increased BUN (48.0 mg/dL vs. 16.0 mg/dL, p = 0.049). Interleukin-6 levels were elevated in S1KO mice (96.5 ng/mL vs. 45.6 ng/mL, p = 0.028) and S1KO-LysMCre mice (35.8 ng/mL vs. 24.5 ng/mL, p = 0.033) compared with controls 12 hours after surgery. Five-day survival in S1KO (33.3% vs. 83.3%, p = 0.025) and S1KO-LysMCre (60% vs. 100%, p = 0.049) mice was decreased compared with controls.
CONCLUSION
Sirtuin 1 deletion increases systemic inflammation in sepsis. Renal mitochondrial dysfunction, kidney injury, and mortality following CLP were all exacerbated by SIRT1 deletion. Similar effects on inflammation and survival were seen following myeloid cell-specific SIRT1 deletion, indicating that SIRT1 activity in myeloid cells may be a significant contributor for the protective effects of SIRT1 in sepsis.
背景
败血症是一种对感染的过度炎症反应，可导致多器官衰竭，最终导致死亡。通常，多器官衰竭的发作是由肾功能障碍引起的。Sirtuin 1（SIRT1）通过抑制炎症和促进线粒体功能来促进细胞应激耐受力。我们假设 SIRT1 在限制导致败血症器官衰竭的炎症反应方面发挥着重要作用，主要通过在髓样细胞中的表达。
方法
我们在 C57BL/6J 背景下对全身 SIRT1 敲除（S1KO）和髓样细胞特异性 S1KO（S1KO-LysMCre）小鼠进行盲肠结扎和穿刺（CLP）。通过酶联免疫吸附试验定量测定血清白细胞介素（IL）-6。使用 Oxygraph-2k（Oroboros Instruments，因斯布鲁克，奥地利）测量肾线粒体复合物活性。从血清中测量血尿素氮（BUN）。监测生存时间长达 5 天。
结果
CLP 后，S1KO 小鼠的肾线粒体复合物 I 依赖性呼吸能力（241.7 对 418.3 mmolO2/mg/min，p = 0.018）和肾线粒体复合物 II 依赖性呼吸能力（932.3 对 1178.4，p = 0.027）降低，以及脂肪酸氧化率降低（187.3 对 250.3，p = 0.022）。Sirtuin 1 敲除小鼠的 BUN 也升高（48.0 mg/dL 对 16.0 mg/dL，p = 0.049）。与对照组相比，S1KO 小鼠（96.5 ng/mL 对 45.6 ng/mL，p = 0.028）和 S1KO-LysMCre 小鼠（35.8 ng/mL 对 24.5 ng/mL，p = 0.033）的白细胞介素-6 水平升高。S1KO（33.3% 对 83.3%，p = 0.025）和 S1KO-LysMCre（60% 对 100%，p = 0.049）小鼠的 5 天生存率均低于对照组。
结论
Sirtuin 1 缺失增加败血症中的全身炎症。CLP 后肾线粒体功能障碍、肾损伤和死亡率均因 SIRT1 缺失而加剧。髓样细胞特异性 SIRT1 缺失也表现出类似的炎症和存活效果，表明髓样细胞中 SIRT1 的活性可能是 SIRT1 在败血症中保护作用的重要贡献因素。
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