Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung
Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung
复制标题
活化的多形核中性粒细胞外泌体：导致肺部基质破坏和疾病的致病实体
DOI：
10.1016/j.cell.2018.12.002
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发表时间：
2019-01-10
期刊：
影响因子：
64.5
通讯作者：
Blalock, J. Edwin
中科院分区：
文献类型：
--
作者：
Genschmer, Kristopher R.;Russell, Derek W.;Blalock, J. Edwin
在这里，我们描述了一个新型的致病实体，即活化的PMN（多形核白细胞，即中性粒细胞）衍生的外泌体。这些CD63（+）/CD66b（+）纳米层在PMN脱粒过程中获得表面结合的中性粒细胞弹性酶（NE），NE以抗抗α1-抗抗蛋白酶（alpha 1AT）的抗构型为导向。这些外泌体分别通过整合素MAC-1和NE结合并降解细胞外基质（ECM），从而导致慢性阻塞性肺疾病（COPD）的标志。由于ECM靶向和Alpha 1AT抗性，外泌体NE比游离NE更有效。重要的是，此类PMN衍生的外泌体存在于患有COPD的受试者但没有健康对照的受试者的临床标本中，并且能够以NE驱动的方式将类似COPD的表型从人类转移到小鼠。对于ECM重塑的另一种中性粒细胞驱动的疾病（支气管肺发育不良[BPD]）也观察到了类似的发现。这些发现揭示了外泌体在ECM稳态疾病（例如COPD和BPD）的发病机理中的作用，这为蛋白水解损伤提供了关键的机制。
Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63(+)/CD66b(+) nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to alpha 1-antitrypsin (alpha 1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and alpha 1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.