Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India.
King George's Medical University, Lucknow, India.
Inflammation. 2019 Dec;42(6):2286-2296. doi: 10.1007/s10753-019-01093-z.
Neutrophil survival and oxidative stress during inflammatory conditions are linked to tissue damage. The present study explores less understood role of catalase, the enzyme catalysing hydrogen peroxide decomposition, in neutrophil survival/death. Importantly, inhibition of catalase activity following S-glutathionylation in the PMA, NO, or zymosan-activated neutrophils or treatment with catalase inhibitor led to neutrophil death. On the contrary, introducing reducing environment by TCEP rescued catalase activity and significantly improved neutrophil survival. Furthermore, augmentation in ROS generation by NOX-2 activation or induction of mitochondrial ROS by Antimycin-A induced catalase S-glutathionylation and cell death, which was prevented in the neutrophil cytosolic factor1 (NCF-1-/-) cells or was rescued by MitoTEMPO, a mitochondrial ROS scavenger, thus, suggesting a correlation between catalase S-glutathionylation/activity inhibition and reduced neutrophil survival. Altogether, enhanced NOX2 activation/mitochondrial dysfunction led to reduced survival of human and mice neutrophils, due to HO accumulation, S-glutathionylation of catalase, and reduction in its enzymatic activity. The present study thus demonstrated mitigation of catalase activity under oxidative stress-impacted neutrophil survival.
在炎症条件下，中性粒细胞的存活和氧化应激与组织损伤有关。本研究探讨了过氧化氢酶（催化过氧化氢分解的酶）在中性粒细胞存活/死亡中的作用，这一作用目前还不太清楚。重要的是，在 PMA、NO 或酵母聚糖激活的中性粒细胞中经 S-谷胱甘肽化作用抑制过氧化氢酶活性，或用过氧化氢酶抑制剂处理，会导致中性粒细胞死亡。相反，通过 TCEP 引入还原环境可恢复过氧化氢酶活性，并显著提高中性粒细胞的存活率。此外，通过激活 NOX-2 增加 ROS 生成或通过 Antimycin-A 诱导线粒体 ROS 生成，诱导过氧化氢酶 S-谷胱甘肽化和细胞死亡，在中性粒细胞胞质因子 1（NCF-1-/-）细胞中这种情况可以被阻止，或通过线粒体 ROS 清除剂 MitoTEMPO 进行挽救，因此，这表明过氧化氢酶 S-谷胱甘肽化/活性抑制与中性粒细胞存活率降低之间存在相关性。总之，由于 HO 积累、过氧化氢酶的 S-谷胱甘肽化以及其酶活性的降低，增强的 NOX2 激活/线粒体功能障碍导致人和小鼠中性粒细胞的存活率降低。因此，本研究表明在氧化应激影响中性粒细胞存活的情况下，可以减轻过氧化氢酶的活性。
