Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock
Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock
复制标题
前沿科学：巨噬细胞衍生的外泌体促进失血性休克后中性粒细胞坏死性凋亡
DOI：
10.1189/jlb.3hi0517-173r
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发表时间：
2018-02-01
影响因子：
5.5
通讯作者：
Fan, Jie
中科院分区：
文献类型：
--
作者：
Jiao, Yang;Li, Zhigang;Fan, Jie
出血性休克（HS）使患者易于通过尚不清楚的机制发展成全身炎症反应综合征（SIRS）和多器官功能障碍综合征（MODS）。细胞坏死性凋亡是一种受调节的炎性细胞死亡形式，是控制先天免疫细胞（如多形核中性粒细胞（PMN））释放炎性介质的机制之一，并严重调节炎症的进展。本研究旨在探讨肺泡巨噬细胞（AM phi）对HS后中性粒细胞坏死性凋亡的影响及其机制。利用在体和离体HS模型，我们揭示了一种新的功能，休克激活的AM phi在促进中性粒细胞坏死性凋亡。我们证明，从HS激活的AM phi释放的外泌体主要诱导PMN内NADPH氧化酶衍生的活性氧（ROS）产生，随后促进坏死性凋亡。这些发现探索了一种先前未鉴定的AM phi-PMN串扰途径，其导致增强的PMN坏死性凋亡和随后的过度HS后肺部炎症。因此，以PMN死亡通路为靶点可能成为HS后SIRS治疗的新策略。
Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AM phi) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AM phi in promoting PMN necroptosis. We demonstrate that exosomes released from HS-activated AM phi induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AM phi-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS.