Sirtuin 1 deletion increases inflammation and mortality in sepsis.
Sirtuin 1 deletion increases inflammation and mortality in sepsis.
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DOI：
10.1097/ta.0000000000003751
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发表时间：
2022-11-01
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脓毒症是对感染的一种高炎症反应，可导致多器官衰竭并最终死亡。通常，多器官衰竭的发生是肾功能障碍的前兆。Sirtuin 1(SIRT1)通过抑制炎症和促进线粒体功能促进细胞应激恢复能力。我们假设SIRT1在限制炎症反应中发挥重要作用，炎症反应主要通过髓系细胞的表达而导致脓毒症器官衰竭。以C57BL/6J小鼠为研究对象，对SIRT1 KO(S1KO)和髓系细胞特异性SIRT1 KO(S1KO-LysMCre)小鼠进行盲肠结扎穿孔(CLP)。用双抗体夹心酶联免疫吸附试验测定血清IL6水平。用Oroboros Oxygraph-2k测定肾脏线粒体复合体活性。从血清中测定BUN。存活监测时间长达5天。在CLP后，S1KO小鼠肾脏线粒体复合体I(241.7比418.3 mmolO2/mg/分钟，p=0.018)和II(932.3比1178.4，p=0.027)依赖的呼吸量减少，脂肪酸氧化率降低(187.3比250.3，p=0.022)。S1KO小鼠BUN也升高(48.0 mg/dL比16.0 mg/dL，p=0.049)。术后12小时，S1KO小鼠(96.5 ng/mLvs45.6 ng/mLvs45.6 ng/mLp=0.028)和S1KO-LysMCre小鼠(35.8 ng/mLvs24.5 ng/mLp=0.033)的IL-6水平明显升高。与对照组相比，S1KO(33.3%vs 83.3%，p=0.025)和S1KO-LysMCre(60%vs 100%，p=0.049)小鼠5d存活率降低。SIRT1缺失会增加脓毒症患者的全身炎症反应。CLP后肾脏线粒体功能障碍、肾脏损伤和死亡率均因SIRT1缺失而加重。髓系细胞特异性SIRT1缺失后对炎症和生存的影响相似，表明髓系细胞中的SIRT1活性可能是SIRT1在脓毒症中保护作用的重要因素。基础科学研究#脓毒症中巨噬细胞特异性的#SIRT1缺失增加了CLP小鼠模型的炎症和死亡率。
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. We performed cecal ligation and puncture (CLP) on whole body SIRT1 KO (S1KO) and myeloid cell-specific SIRT1 KO (S1KO-LysMCre) mice on a C57BL/6J background. Serum IL6 was quantified by ELISA. Renal mitochondrial complex activity was measured using Oroboros Oxygraph-2k. BUN was measured from serum. Survival was monitored for up to 5 days. Following CLP, S1KO mice had decreased renal mitochondrial complex I (241.7 vs 418.3 mmolO2/mg/min, p=0.018) and II (932.3 vs 1178.4, p=0.027)-dependent respiratory capacity, as well as reduced rates of fatty acid oxidation (187.3 vs 250.3, p=0.022). S1KO mice also had increased BUN (48.0mg/dL vs. 16.0mg/dL, p=0.049). IL6 levels were elevated in S1KO mice (96.5ng/mL vs 45.6ng/mL, p=0.028) and S1KO-LysMCre mice (35.8ng/mL vs 24.5ng/mL, p=0.033) compared to controls 12 hours after surgery. 5d survival in S1KO (33.3% vs 83.3%, p=0.025) and S1KO-LysMCre (60% vs 100%, p=0.049) mice was decreased compared to controls. SIRT1 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. Basic Science Research Macrophage-specific deletion of #SIRT1 in #sepsis increases inflammation and mortality in a murine model of CLP.