Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques.
Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques.
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DOI：
10.1111/cmi.12428
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发表时间：
2015-08
影响因子：
3.4
通讯作者：
Flynn JL
中科院分区：
文献类型：
--
作者：
Mattila JT;Maiello P;Sun T;Via LE;Flynn JL
中性粒细胞在结核病(TB)中的作用，以及中性粒细胞是否表达颗粒酶B(GrzB)，这是一种与细胞毒性T细胞相关的促凋亡酶，存在争议。我们检测了结核分枝杆菌感染的食蟹猴和人类外周血(PB)和肺肉芽肿中的中性粒细胞，以确定分枝杆菌产物或促炎因子是否诱导中性粒细胞grzB的表达。我们在猕猴和人类肉芽肿中发现了大量表达grzB的中性粒细胞，这些细胞含有比T细胞更多的grzB+颗粒。中性粒细胞，而不是T细胞，grzB的高表达与细菌负荷增加相关。尽管未受刺激的外周血中性粒细胞缺乏grzB的表达，但在结核杆菌、结核杆菌培养滤液蛋白或来自大肠杆菌的脂多糖作用下，grzB的表达增加。穿孔素是颗粒酶介导的T细胞杀伤所必需的，但在外周血或中性粒细胞肉芽肿中未观察到穿孔素。然而，用酶联免疫斑点法测定，受刺激的外周血中性粒细胞分泌grzB。纯化的grzB没有杀菌或抑菌作用，提示分泌的中性粒细胞grzB作用于细胞外靶点，潜在地促进中性粒细胞在细胞外基质中的迁移，并调节其他类型细胞的凋亡或激活。这些数据表明，分枝杆菌产物和肉芽肿的促炎环境上调了中性粒细胞grzB的表达，并提示了结核病中性粒细胞生物学以前未被认识的一个方面。
The role of neutrophils in tuberculosis (TB), and whether neutrophils express granzyme B (grzB), a pro-apoptotic enzyme associated with cytotoxic T cells, is controversial. We examined neutrophils in peripheral blood (PB) and lung granulomas of Mycobacterium tuberculosis-infected cynomolgus macaques and humans to determine whether mycobacterial products or pro-inflammatory factors induce neutrophil grzB expression. We found large numbers of grzB-expressing neutrophils in macaque and human granulomas and these cells contained more grzB+ granules than T cells. Higher neutrophil, but not T cell, grzB expression correlated with increased bacterial load. Although unstimulated PB neutrophils lacked grzB expression, grzB expression increased upon exposure to M. tuberculosis bacilli, M. tuberculosis culture filtrate protein or lipopolysaccharide from Escherichia coli. Perforin is required for granzyme-mediated cytotoxicity by T cells, but was not observed in PB or granuloma neutrophils. Nonetheless, stimulated PB neutrophils secreted grzB as determined by enzyme-linked immunospot assays. Purified grzB was not bactericidal or bacteriostatic, suggesting secreted neutrophil grzB acts on extracellular targets, potentially enhancing neutrophil migration through extracellular matrix and regulating apoptosis or activation in other cell types. These data indicate mycobacterial products and the pro-inflammatory environment of granulomas up-regulates neutrophil grzB expression and suggests a previously unappreciated aspect of neutrophil biology in TB.