Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: Role of HMGB1-TLR4 signaling
Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: Role of HMGB1-TLR4 signaling
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DOI：
10.4049/jimmunol.178.10.6573
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
Wilson, Mark A.
中科院分区：
文献类型：
--
作者：
Fan, Jie;Li, Yuehua;Wilson, Mark A.
失血性休克/复苏（HS/R）诱导的活性氧（ROS）产生在失血后炎症和组织损伤中起重要作用。我们最近报道，HS/R激活的中性粒细胞（PMN）通过释放ROS，在介导肺泡巨噬细胞激活和肺部炎症中发挥重要的信号传导功能。PMN的NAD（P）H氧化酶被认为是HS/R后ROS的一个重要来源。Toll样受体4（TLR4）通过介导对细菌内毒素和多种内源性配体（包括高迁移率族蛋白B1（HMGB1））的反应，处于微生物性和无菌性炎症的界面。近期研究表明，HMGB1是HS/R和器官缺血/再灌注后炎症的早期介质。在本研究中，我们验证了HS/R通过HMGB1/TLR4信号通路激活PMN中NAD（P）H氧化酶这一假说。我们证实，在野生型小鼠中，HS/R以NAD（P）H氧化酶的p47（phox）亚基磷酸化的形式诱导PMN的NAD（P）H氧化酶激活；在TLR4突变的C3H/HeJ小鼠中，这种诱导显著减弱。HS/R后最早2小时，肺、肝和血清中的HMGB1水平就升高。抗HMGB1中和抗体可阻止HS/R诱导的PMN中p47（phox）磷酸化。此外，用重组HMGB1体外刺激PMN可导致NAD（P）H氧化酶的TLR4依赖性激活，以及通过MyD88 - IRAK4 - p38 MAPK和MyD88 - IRAK4 - Akt信号通路增加ROS产生。因此，由HS/R诱导且由HMGB1/TLR4信号介导的PMN的NAD（P）H氧化酶激活是出血后PMN介导的炎症和器官损伤的一个重要机制。《免疫学杂志》，2007年，178卷：6573 - 6580页。
Hemorrhagic shock/resuscitation (HS/R)-induced generation of reactive oxygen species (ROS) plays an important role in posthemorrhage inflammation and tissue injury. We have recently reported that HS/R-activated neutrophils (PMN), through release of ROS, serve an important signaling function in mediating alveolar macrophage priming and lung inflammation. PMN NAD(P)H oxiclase has been thought to be an important source of ROS following HS/R. TLR4 sits at the interface of microbial and sterile inflammation by mediating responses to both bacterial endotoxin and multiple endogenous ligands, including high-mo bility group box 1 (HMGB1). Recent studies have implicated HMGB1 as an early mediator of inflammation after HS/R and organ ischemia/ reperfusion. In the present study, we tested the hypothesis that HS/R activates NAD(P)H oxidase in PMN through HMGB1/TLR4 signaling. We demonstrated that HS/R induced PMN NAD(P)H oxidase activation, in the form of phosphorylation of p47(phox)subunit of NAD(P)H oxidase, in wild-type mice; this induction was significantly diminished in TLR4-mutant C3H/HeJ mice. HMGB1 levels in lungs, liver, and serum were increased as early as 2 h after HS/R. Neutralizing Ab to HMGB1 prevented HS/R-induced phosphorylation of p47(phox) in PMN. In addition, in vitro stimulation of PMN with recombinant HMGB1 caused TLR4-dependent activation of NAD(P)H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-Akt signaling pathways. Thus, PMN NAD(P)H oxidase activation, induced by HS/R and as mediated by HMGBI/TLR4 signaling, is an important mechanism responsible for PMN-mediated inflammation and organ injury after hemorrhage. The Journal of Immunology, 2007, 178: 6573-6580.