The many levels on which melatonin regulates inflammation and immune function
Although we primarily think of melatonin as a regulator of the circadian rhythm and our most primitive protective antioxidant,[1],[2] the role it plays in the body is far more encompassing than this. In addition to regulating the sleep cycle, melatonin impacts reproductive function,[3] physical growth,[4] bone formation,[5] brain health,[6] metabolism,[7],[8] oral health,[9] and of greatest relevance to the discussion here, our immune system function.[10]
Much like other key hormones and signaling molecules, melatonin has multiple receptors that are found in nearly every system of the body including the cells of the immune system.[11],[12] Although melatonin is primarily produced by the pineal gland, research suggests it is also produced in the bone marrow,[13] thymus,[14] lymphocytes,[15] and various cells of the gastrointestinal tract – each of which influence immune function.[16],[17]
Well-established by numerous studies are the declining levels and altered rhythms of melatonin with increasing age.[18],[19] Age-related decreases in melatonin as well as other critical antioxidants including CoQ10 and glutathione are a factor leading to the declining function of our cells, organs, and systems overall, contributing to numerous diseases we see with advancing age.[20],[21],[22] Although each of these antioxidants are important for normal healthy immune function,[23],[24],[25] melatonin comes to the forefront as a critical factor that affects our susceptibility and response to infections.
Herein, we step through the mechanisms by which melatonin may impact immune function and inflammation.
The Circadian Rhythm and the Immune Response
Melatonin is one of many hormones that have a circadian variation in the human body. Opposite to it, cortisol and dehydroepiandrosterone (DHEA) oscillate cyclically in a 24-hour period, having daytime peaks.[26],[27] Although we tend to think of these three hormones the most when it comes to the day-to-day cyclic variation, nearly every hormone in the body varies diurnally,[28] with each of them influencing each other as well.
Levels of nearly all immune cell subpopulations and the signaling cytokines they secrete have a circadian variation, influenced by sleep.[29] Nocturnal sleep is associated with an acute lowering of monocytes, natural killer cells, and all lymphocyte subsets, followed by a rebound to daytime levels the following afternoon and evening.[30] When the normal nocturnal sleep period is absent, both the dip and rise of many of these lymphocytes is attenuated. Pro-inflammatory cytokines and undifferentiated naïve T cells peak during early nocturnal sleep while levels of anti-inflammatory cytokines and cytotoxic natural killer cells peak during daytime wakefulness.[31] Prolonged sleep disruption has been established by several human studies to promote a pro-inflammatory state.[32],[33],[34]
In severe illness such as sepsis, melatonin secretion is impaired, while in other critical care settings, it often is dysregulated.
Melatonin influences the circadian variation of the immune response and levels of inflammatory mediators.[35],[36],[37] Conversely, inflammatory cytokines such as tumor necrosis factor (TNF)‐α influence nocturnal melatonin production as well.[38],[39] In severe illness such as sepsis, melatonin secretion is impaired,[40] while in other critical care settings, it often is dysregulated.[41],[42] Certain viral infections have also been shown to disrupt the circadian rhythm, which can additionally lead to increased viral replication.[43],[44]
Animal studies have shown that melatonin supplementation helps attenuate the proinflammatory effects of sleep deprivation and inflammatory response to triggers such as lipopolysaccharide, also reducing immunocyte infiltration and tissue damage in the lungs.[45],[46]
Studies suggest that sleep and/or melatonin administration enhances interactions between antigen-presenting cells and T helper cells,[47] promoting immunological memory much like sleep does for neurobehavioral memory.[48] Melatonin also has been observed to increase natural killer cell production and activity as well as antibody-dependent cellular cytotoxicity.[49],[50],[51] Melatonin not only opposes the wakefulness actions of cortisol, it also antagonizes its immunosuppressive effects.[52]
Melatonin and Inflammation
One mechanism by which melatonin may attenuate the severity of inflammation is through inhibition of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome contributes to the pathology in numerous conditions associated with chronic, low-grade inflammation[53] including type 2 diabetes,[54] non-alcoholic steatohepatitis,[55] and Alzheimer’s disease;[56] each of which melatonin has been shown to help protect against.[57],[58],[59],[60] Although some level of NLRP3 activation is important for the normal, protective response to microbial invaders,[61] it also can be a mediator of excessive inflammation and the pathology that ensues.[62],[63]
Inhibition of the NLRP3 inflammasome is one mechanism by which melatonin has been shown to reduce airway inflammation associated with allergies, COPD, radiation, and LPS-induced acute lung injury.
Animal models of atherosclerosis,[64] osteoporosis,[65] diabetic cardiomyopathy,[66] radiation injury,[67] and more[68] show melatonin has protective effects via inhibition of NLRP3 inflammasome activation. Inhibition of the NLRP3 inflammasome is one mechanism by which melatonin has been shown in animals to reduce airway inflammation associated with allergies, chronic obstructive pulmonary disease (COPD), radiation, and lipopolysaccharide (LPS)-induced acute lung injury.[69],[70],[71],[72]
Melatonin has also been shown in multiple studies to have anti-inflammatory effects by increasing levels of interleukin (IL)-10 and reducing TNF-α.[73],[74],[75] Cellular studies with human blood samples found that treatment with melatonin (at levels similar to what can be achieved physiologically) attenuated the mitochondrial dysfunction, oxidative stress, and cytokine response to LPS.[76] Melatonin also helps reduce the body’s overproduction of nitric oxide (NO).[77] Although NO helps mediate the body’s antiviral response, it also contributes to infection-related pathology.[78]
Multiple human studies have shown that in conditions associated with chronic inflammation such as type 2 diabetes, periodontitis, and multiple sclerosis, melatonin reduces levels of C-reactive protein (CRP) and/or various pro-inflammatory cytokines.[79],[80],[81],[82] Acute application of melatonin as a therapy at doses ranging from 3 to 20 mg/day also has been shown to reduce markers of inflammation in surgical settings.[83],[84],[85] Results from a 2019 meta-analysis of randomized controlled trials also validates melatonin as an anti-inflammatory therapy, finding that supplementation with three to 25 mg of melatonin for four weeks or more significantly decreased TNF-α and IL-6 levels.[86]
Several human studies have demonstrated that endogenously higher melatonin levels or melatonin as a therapy is associated with positive outcomes in non-infectious respiratory illness of an inflammatory nature.
Several human studies have demonstrated that endogenously higher melatonin levels or melatonin as a therapy is associated with positive outcomes in non-infectious respiratory illness of an inflammatory nature. In patients with COPD and bronchial asthma, lower levels of melatonin and increased oxidative stress have been shown during periods of disease exacerbation (severe enough to require hospitalization).[87]
A 1995 review, published in the Lancet, discussed two case reports of chronic sarcoidosis treated with 20 mg of melatonin daily.[88] In both of these individuals, there were dramatic improvements not only in difficulty breathing but also the high-resolution computed tomography images of the chest and lymph node involvement. In one of these cases, after ceasing therapy for several months, the difficulty breathing and skin lesions (which often accompany the disease) returned and were resolved by resuming the 20 mg of melatonin daily.
Melatonin and Infections
Cellular and animal studies suggest that antiviral activities attributed to melatonin are primarily due to its immunomodulatory and antioxidant effects.[89]
Treatment with melatonin has been shown to reduce viral load and/or virus-related pathology and death in several animal disease models.[90],[91],[92] Melatonin has been shown to have synergistic effects with the antiviral medication ribavirin in the treatment of influenza in animals, significantly increasing survival rate.[93]
The inflammation cascade associated with sepsis not only acutely depletes the body’s protective antioxidants, the cytokines associated with it also have an effect of suppressing pineal melatonin production.
To the knowledge of this author, no studies have been done investigating melatonin as a monotherapy in humans for the treatment or prevention of viral infections, however in combination with a mixture of substances extracted from Aspergillus sp., antiviral properties have been demonstrated in humans.[94]
Much like the setting of viral infections, melatonin’s actions as an antioxidant and immunomodulatory substance have been put forth as mechanisms by which it impacts bacterial infections.[95] It has been suggested that melatonin also affects bacterial viability by altering levels of intracellular substrates, permeability of cellular membranes, or by acting as a pro-oxidant and forming stable radicals.[96]
Low levels of antibacterial action have also been demonstrated against gram-negative and -positive bacteria at concentrations ranging from 0.13 to 0.53 mM.[97] This should be taken in context with physiological melatonin levels which, in plasma, are typically less than 2 x 10-7 mM at their peak.[98]
Melatonin’s anti-inflammatory, immunomodulatory, and antioxidant properties also contribute to the improvements that have been seen with melatonin as a treatment for sepsis,[99] where infection-triggered inflammation and oxidative stress can lead to organ damage and failure systemically. The inflammation cascade associated with sepsis not only acutely depletes the body’s protective antioxidants including vitamin C,[100],[101] the cytokines associated with it such as TNF-α and IL-1β also have an effect of suppressing pineal melatonin production.[102],[103],[104] Because melatonin is an important trigger for the synthesis of other antioxidants, including glutathione, and numerous antioxidant enzymes, further problems ensue.[105],[106]
Currently, a clinical trial is underway evaluating melatonin (50 mg once daily) versus vitamin C (1 g every 6 hours), vitamin E (400 IU every 8 hours), N-acetylcysteine (1200 mg every 12 hours), and placebo given as oral therapies over a period of five days as an adjunctive to conventional treatments in critically ill patients with septic shock.[107]
Melatonin has a high safety profile which includes settings such as pediatrics, the elderly, intensive-care, and surgical settings.[108],[109],[110] Further information on the wide array of clinical research pertaining to melatonin as a sleep-supportive agent and its higher-dose use can be found in previous Nutrition In Focus blog posts.
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