Department of Studies in Biochemistry, University of Mysore, Mysore, India.
Department of Studies and Research in Biochemistry, Tumkur University, Tumakuru, India.
J Pineal Res. 2020 Oct;69(3):e12676. doi: 10.1111/jpi.12676. Epub 2020 Aug 18.
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.
褪黑素是一种生物钟激素，通过调节氧化还原系统，可调节癌症、动脉粥样硬化、呼吸障碍和微生物感染等人类疾病。褪黑素通过与免疫系统交流并影响中性粒细胞来抗感染和炎症，从而表现出先天的免疫调节作用。然而，在趋化、氧化爆发、吞噬和中性粒细胞胞外陷阱（NET）形成过程中，维持中性粒细胞的氧化还原平衡和活性氧（ROS）的产生至关重要。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方面非常重要。在自身免疫性疾病、神经退行性疾病、糖尿病和微生物感染等临床情况下，中性粒细胞中的细胞内 GSH 水平和谷胱甘肽还原酶（GR）活性降低，导致中性粒细胞功能障碍。因此，我们假设像褪黑素这样的氧化还原调节剂可以在 GSH 和 GR 活性缺乏的情况下保护中性粒细胞的健康和功能。我们展示了褪黑素的双重作用，它通过减少 ROS 的产生来保护中性粒细胞免受氧化应激诱导的凋亡；相反，它通过调节 ROS 水平，在体外和体内恢复吞噬、脱颗粒和 NETosis 等中性粒细胞功能，从而在 GSH 和 GR 活性缺乏的中性粒细胞中恢复中性粒细胞功能。褪黑素通过充当平行的氧化还原系统来恢复 GSH 氧化还原系统，特别是 GR 活性，从而减轻 LPS 诱导的中性粒细胞功能障碍。我们的研究结果表明，褪黑素可以通过恢复中性粒细胞功能，成为治疗慢性疾病条件下免疫功能障碍和微生物感染（包括病毒）的潜在辅助治疗方法。此外，褪黑素可能是一种有前途的免疫系统增强剂，可用于对抗当前 COVID-19 等前所未有的大流行。然而，为了解决褪黑素的临床应用问题，还需要进一步的研究。
