From the Department of Anesthesiology and Intensive Care Unit, the First Affiliated Hospital (F.S., J.H., Z.C., B.C., R.L., P.C., Y.S., X.F.) Department of Anesthesiology and Intensive Care Unit, Sir Run Run Shaw Hospital (H.W.), School of Medicine, Zhejiang University, Hangzhou, China.
Anesthesiology. 2018 Aug;129(2):311-320. doi: 10.1097/ALN.0000000000002196.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11-dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1β secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11-dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome.
A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2), or nucleotide-binding oligomerization domain-like receptor protein-3-deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11).
Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 ± 3% in wild-type vs. 10 ± 3% in S1pr2, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035).
S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis.
本文的新发现：背景：细胞焦亡是一种促炎程序性细胞死亡方式，可导致细胞因子风暴。依赖于半胱天冬酶-11 的巨噬细胞细胞焦亡有助于脓毒症患者的死亡率。鞘氨醇-1-磷酸受体 2（S1PR2）信号可放大内毒素诱导的炎症中的白细胞介素-1β分泌。在这里，我们假设 S1PR2 信号增加依赖于半胱天冬酶-11 的巨噬细胞细胞焦亡，并使革兰氏阴性脓毒症的结局恶化。
通过腹腔注射大肠杆菌诱导革兰氏阴性脓毒症模型。用大肠杆菌处理从野生型、S1pr2 缺陷型（S1pr2）或核苷酸结合寡聚化结构域样受体蛋白 3 缺陷型小鼠分离的原代腹腔巨噬细胞。评估这些细胞中的半胱天冬酶-11 活化、巨噬细胞细胞焦亡和 Ras 同源基因家族成员 A-鸟苷三磷酸水平。此外，在革兰氏阴性脓毒症患者（n=11）中确定单核细胞半胱天冬酶-4（半胱天冬酶-11 的类似物）的表达及其与 S1PR2 表达的相关性。
S1PR2 的基因缺失显著提高了存活率（野生型为 2/10[20%]，S1pr2 为 7/10[70%]，P=0.004），并降低了腹腔巨噬细胞细胞焦亡（焦亡率：野生型为 35±3%，S1pr2 为 10±3%，P<0.001）。S1PR2 缺陷细胞中半胱天冬酶-11 活化减少导致巨噬细胞细胞焦亡减少。此外，RhoA 抑制剂消除了野生型或 S1PR2 过表达细胞中放大的半胱天冬酶-11 活化。在革兰氏阴性脓毒症患者中，与非脓毒症对照相比，单核细胞中的 caspase-4 显著增加，并且与 S1PR2 呈正相关（r=0.636，P=0.035）。
S1PR2 缺陷降低了大肠杆菌脓毒症中巨噬细胞细胞焦亡并提高了生存率。这些有益作用归因于 S1PR2 缺陷巨噬细胞中半胱天冬酶-11 的活化减少。S1PR2 和半胱天冬酶-11 可能是脓毒症治疗的有希望的新靶点。
