Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2.
Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2.
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DOI：
10.1084/jem.20141813
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发表时间：
2015-08-24
期刊：
影响因子：
--
通讯作者：
Bae YS
中科院分区：
文献类型：
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作者：
Lee SK;Kim SD;Kook M;Lee HY;Ghim J;Choi Y;Zabel BA;Ryu SH;Bae YS
Lee等人发现，在小鼠实验性脓毒症期间，磷脂酶D2缺乏增加存活率并减少器官损伤，这可以用CXCR 2拮抗剂逆转。因此，靶向PLD 2可以为脓毒症患者提供治疗。我们使用PLD 2 −/−小鼠和PLD 2特异性抑制剂确定了磷脂酶D2（PLD 2）在高致死性脓毒症小鼠模型中的宿主防御功能。PLD 2缺陷不仅增加存活率，而且减少实验性脓毒症期间的重要器官损伤。在PLD 2 −/−小鼠中，几种炎性细胞因子（TNF、IL-1β、IL-17和IL-23）和趋化因子CXCL 1的产生以及免疫组织、肾脏和肝脏中的细胞凋亡显著减少。在PLD 2 −/−小鼠中，杀菌活性显著增加，这是由中性粒细胞胞外陷阱形成增加和组蛋白3的瓜氨酸化通过肽基精氨酸脱亚胺酶活化介导的。在PLD 2 −/−小鼠中，中性粒细胞向肺的募集显著增加。此外，LPS诱导的G蛋白偶联受体激酶2（GRK 2）的诱导和CXCR 2的下调在PLD 2 −/−小鼠中显著减弱。一种CXCR 2选择性拮抗剂消除了实验性脓毒症期间PLD 2缺乏所赋予的保护作用，这表明增强的CXCR 2表达（可能由中性粒细胞中GRK 2下调驱动）促进了PLD 2 −/−小鼠的存活。此外，与转移的WT中性粒细胞相比，过继转移的PLD 2 −/−中性粒细胞显著保护WT受体免于败血症诱导的死亡。我们认为中性粒细胞中的PLD 2对于实验性脓毒症的发病机制是必不可少的，并且靶向PLD 2的药物制剂可能被证明对脓毒症患者有益。
Lee et al. find that phospholipase D2 deficiency increases survival and decreases organ damage during experimental sepsis in mice which could be reversed with a CXCR2 antagonist. Thus, targeting PLD2 may offer therapeutics for septic patients. We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2−/− mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apoptosis in immune tissues, kidney, and liver, are markedly decreased in PLD2−/− mice. Bactericidal activity is significantly increased in PLD2−/− mice, which is mediated by increased neutrophil extracellular trap formation and citrullination of histone 3 through peptidylarginine deiminase activation. Recruitment of neutrophils to the lung is markedly increased in PLD2−/− mice. Furthermore, LPS-induced induction of G protein–coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly attenuated in PLD2−/− mice. A CXCR2-selective antagonist abolishes the protection conferred by PLD2 deficiency during experimental sepsis, suggesting that enhanced CXCR2 expression, likely driven by GRK2 down-regulation in neutrophils, promotes survival in PLD2−/− mice. Furthermore, adoptively transferred PLD2−/− neutrophils significantly protect WT recipients against sepsis-induced death compared with transferred WT neutrophils. We suggest that PLD2 in neutrophils is essential for the pathogenesis of experimental sepsis and that pharmaceutical agents that target PLD2 may prove beneficial for septic patients.