Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.
J Leukoc Biol. 2020 Mar;107(3):393-408. doi: 10.1002/JLB.3RI0120-645R. Epub 2020 Jan 28.
Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil-mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.
中性粒细胞激活失调会导致人类疾病。全面抑制中性粒细胞功能或耗竭中性粒细胞都不能提供安全有效的治疗方法。中性粒细胞颗粒胞吐作用在导致招募和细胞损伤的多个步骤中发挥作用，这促使我们的实验室各自开发出分子抑制剂，这些抑制剂可以干扰分泌的特定分子调节剂。这篇综述总结了中性粒细胞颗粒的形成和内容、颗粒货物在中性粒细胞功能反应和中性粒细胞介导的疾病中的作用以及颗粒释放的机制，为我们的胞吐抑制剂的开发提供了依据。我们提供了这些抑制剂在体外和体内抑制颗粒胞吐的证据，并总结了动物数据，表明抑制中性粒细胞胞吐是一种可行的治疗策略。
