Melatonin is a chronobiotic hormone, which can regulate human diseases like cancer, atherosclerosis, respiratory disorders, and microbial infections by regulating redox system. Melatonin exhibits innate immunomodulation by communicating with immune system and influencing neutrophils to fight infections and inflammation. However, sustaining redox homeostasis and reactive oxygen species (ROS) generation in neutrophils are critical during chemotaxis, oxidative burst, phagocytosis, and neutrophil extracellular trap (NET) formation. Therefore, endogenous antioxidant glutathione (GSH) redox cycle is highly vital in regulating neutrophil functions. Reduced intracellular GSH levels and glutathione reductase (GR) activity in the neutrophils during clinical conditions like autoimmune disorders, neurological disorders, diabetes, and microbial infections lead to dysfunctional neutrophils. Therefore, we hypothesized that redox modulators like melatonin can protect neutrophil health and functions under GSH and GR activity–deficient conditions. We demonstrate the dual role of melatonin, wherein it protects neutrophils from oxidative stress‐induced apoptosis by reducing ROS generation; in contrast, it restores neutrophil functions like phagocytosis, degranulation, and NETosis in GSH and GR activity–deficient neutrophils by regulating ROS levels both in vitro and in vivo. Melatonin mitigates LPS‐induced neutrophil dysfunctions by rejuvenating GSH redox system, specifically GR activity by acting as a parallel redox system. Our results indicate that melatonin could be a potential auxiliary therapy to treat immune dysfunction and microbial infections, including virus, under chronic disease conditions by restoring neutrophil functions. Further, melatonin could be a promising immune system booster to fight unprecedented pandemics like the current COVID‐19. However, further studies are indispensable to address the clinical usage of melatonin.

中文翻译：

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褪黑素在功能异常的谷胱甘肽氧化还原系统中恢复中性粒细胞功能并防止细胞凋亡。

褪黑激素是一种时序生化激素，可以通过调节氧化还原系统来调节人类疾病，例如癌症，动脉粥样硬化，呼吸系统疾病和微生物感染。褪黑素通过与免疫系统沟通并影响嗜中性粒细胞抵抗感染和炎症而表现出先天性免疫调节作用。然而，在趋化性，氧化爆发，吞噬作用和嗜中性白细胞胞外陷阱（NET）形成过程中，维持嗜中性白细胞的氧化还原稳态和活性氧（ROS）生成至关重要。因此，内源性抗氧化剂谷胱甘肽（GSH）氧化还原循环在调节中性粒细胞功能中至关重要。在临床状况下，例如自身免疫性疾病，神经系统疾病，糖尿病，中性粒细胞减少了中性粒细胞的细胞内GSH水平和谷胱甘肽还原酶（GR）活性 和微生物感染会导致中性粒细胞功能异常。因此，我们假设褪黑素等氧化还原调节剂可以在GSH和GR活性不足的情况下保护嗜中性粒细胞的健康和功能。我们证明了褪黑素的双重作用，其中它通过减少ROS的生成来保护中性粒细胞免受氧化应激诱导的细胞凋亡。相反，它通过调节体内和体外的ROS水平来恢复中性粒细胞功能，例如吞噬作用，脱粒和GSH和GR活性不足的中性粒细胞的NETosis。褪黑素通过活化GSH氧化还原系统，特别是通过充当平行氧化还原系统的GR活性，减轻LPS诱导的中性粒细胞功能障碍。我们的结果表明，褪黑激素可能是治疗免疫功能障碍和微生物感染（包括病毒，在慢性疾病条件下通过恢复中性粒细胞功能。此外，褪黑激素可能是一种有希望的免疫系统增强剂，可与当前的COVID-19等空前的大流行作斗争。但是，进一步的研究对于解决褪黑激素的临床应用是必不可少的。