Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system

Abstract

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.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…On the other hand, age-related impairment of glutathione peroxidase activity accounts for increased intracellular accumulation of hydrogen peroxide (259). Decreased levels of intracellular glutathione peroxidase (GSH-px), due to impaired GRs activity, leads to neutrophil dysfunction during conditions that are associated with chronic inflammation (260,261). NOX2-independent ROS production in neutrophils is amplified by reagents affecting glutathione homeostasis (262).…”

Melatonin for the Early Treatment of COVID-19: A Narrative Review of Current Evidence and Possible Efficacy

“…Due to its ROS-scavenging and anti-inflammatory properties, melatonin has been both proposed and explored as a treatment for various viral infections with mechanisms that cause an excessive immunoinflammatory response ( 5 , 7 , 8 , 9 ). As a powerful hydroxyl radical scavenger and stimulator of antioxidative enzymes such as glutathione peroxidase and superoxide dismutase, melatonin also provides significant protection against cellular oxidative damage ( 10 , 11 ). Many viruses, including ones that cause a cytokine storm, tend to decrease melatonin synthesis which negatively effects the host’s immune system ( 12 ).…”

Altered immunoemotional regulatory system in COVID-19: From the origins to opportunities

“…Melatonin has also been studied in this regard. Melatonin can rejuvenate the glutathione redox system and restore the function of neutrophils in times of heightened oxidative stress, and therefore has been hypothetically suggested as a potential immune booster in the face of COVID-19 ( NaveenKumar et al, 2020 ).…”