Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis.
Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis.
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DOI：
10.1016/j.immuni.2016.03.003
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发表时间：
2016-04-19
期刊：
影响因子：
32.4
通讯作者：
Watts C
中科院分区：
文献类型：
--
作者：
Matthews SP;McMillan SJ;Colbert JD;Lawrence RA;Watts C
嗜酸性粒细胞现在被认为是多功能的白细胞，提供关键的稳态信号，以维持其他免疫细胞和帮助组织修复。特别的是，嗜酸性粒细胞也表达颗粒定位的毒素和水解酶的军械库，据信有助于炎症性疾病的病理学。嗜酸性粒细胞如何提供其支持功能，同时避免自我造成的伤害是知之甚少。我们已经证明，半胱氨酸蛋白酶抑制剂F（CF）是一个关键的嗜酸性粒细胞的生存因素。来自CF无效小鼠的嗜酸性粒细胞具有缩短的寿命、降低的粒度和扰乱的颗粒形态。在体外，半胱氨酸蛋白酶抑制剂恢复粒度，表明CF控制半胱氨酸蛋白酶活性对正常嗜酸性粒细胞的发展至关重要。CF无效小鼠在过敏性肺部炎症模型中显示出减少的肺部病理学，但也降低了对抗马来丝虫线虫感染的能力。这些数据将CF鉴定为通过确保颗粒完整性促进嗜酸性粒细胞存活和功能的“细胞保护剂”。半胱氨酸蛋白酶抑制剂F是嗜酸性粒细胞的一种新的存活因子蛋白酶活性的调节对于正常嗜酸性粒细胞颗粒的生物发生是至关重要的。在半胱氨酸蛋白酶抑制剂F缺失的小鼠中，嗜酸性粒细胞含有标志性颗粒，该颗粒含有几种有毒的碱性蛋白质，但是它们如何安全地激活和隔离这些毒素还知之甚少。在这项研究中，Watts及其同事表明，半胱氨酸蛋白酶抑制剂F通过调节半胱氨酸蛋白酶确保正常的颗粒蛋白成熟，对嗜酸性粒细胞的活力至关重要。
Eosinophils are now recognized as multifunctional leukocytes that provide critical homeostatic signals to maintain other immune cells and aid tissue repair. Paradoxically, eosinophils also express an armory of granule-localized toxins and hydrolases believed to contribute to pathology in inflammatory disease. How eosinophils deliver their supporting functions while avoiding self-inflicted injury is poorly understood. We have demonstrated that cystatin F (CF) is a critical survival factor for eosinophils. Eosinophils from CF null mice had reduced lifespan, reduced granularity, and disturbed granule morphology. In vitro, cysteine protease inhibitors restored granularity, demonstrating that control of cysteine protease activity by CF is critical for normal eosinophil development. CF null mice showed reduced pulmonary pathology in a model of allergic lung inflammation but also reduced ability to combat infection by the nematode Brugia malayi. These data identify CF as a “cytoprotectant” that promotes eosinophil survival and function by ensuring granule integrity. Cystatin F is a novel survival factor for eosinophils Regulation of protease activity is critical for normal eosinophil granule biogenesis Parasite immunity and allergic lung pathology are reduced in cystatin F null mice Eosinophils contain hallmark granules containing several toxic, basic proteins, but how they safely activate and sequester these toxins is poorly understood. In this study, Watts and colleagues show that cystatin F is critical for eosinophil viability by ensuring normal granule protein maturation through regulation of cysteine proteases.