The central master circadian clock is located in the suprachiasmatic nucleus (SCN). The output of this system is synchronized to 24 hours by the light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system that controls the cyclic production of melatonin in the pineal gland. This photoperiod-based regulation obviously generates also melatonin seasonal rhythms Coomans CP et al., 2014. As a pleiotropic molecule, melatonin may influence also the immune system, an effect that was first described 30 years ago Maestroni G et al., 1986. Since then, the immunoregulatory role of melatonin has been widely confirmed and extended in various animal models and also in humans Habbal OA, Al-Jabri AA, 2009.
Most recently, the journal Cell published an interesting study suggesting that melatonin contributes to the seasonality of multiple sclerosis (MS) relapses Farez MF et a., 2015. First of all, the authors reported that clinical disease activity in MS patients shows an inverse correlation with melatonin levels which peaks in autumn and winter. Then they treated mice with experimental autoimmune encephalitis (EAE), an animal model for MS, and found that melatonin had a protective effect. However, in this experiment a pharmacological dose of melatonin was used (5mg/kg). Therefore, the effect they observed might be biased by another action of melatonin, i.e. by its powerful antioxidant activity that usually is most evident at high, non-physiological concentrations Amir-Aslani B, Ghobadi S, 2016 .
Farez and collaborators went on and found that melatonin suppresses in vitro the generation of Th17 cells by acting via its membrane receptors in NFIL3-dependent fashion. Moreover, melatonin could promote Tr1 cell differentiation by activating ROR-alpha and Erk1/2 signaling which controls IL-10 expression. In these experiments the concentration of melatonin was 2 ng/ml, a supra-physiological level.
MS is thought to be an autoimmune disease of the CNS resulting from the destruction of myelin by autoreactive CD4+ T cells producing interferon (IFN)-γ (Th1 cells) or IL-17 (Th17 cells). In addition, deficits in Tregs and IL-10–secreting Tr1 cells have been described in MS. Thus, the conclusion drawn by the authors was that melatonin, whose levels show seasonal variability, controls the balance between pathogenic and regulatory T cells. These findings suggest that melatonin may exert an important immunoregulatory effect in humans by acting on specific membrane and/or nuclear receptors at physiological concentration. In my opinion, this might be by far one of the most important physiological effects of melatonin. If confirmed, it would have important implications in most autoimmmune disorders. Consistently, many years ago, we found that pinealectomy exacerbated type 1 diabetes in mice while melatonin treatment exerted a protective effect Conti A, Maestroni G, 1996. The very same mechanism, i.e., the ability of melatonin to boost T regulatory cells might also explain its negative effect in a model of T cell leukemia Conti A, Maestroni G, 1998.
All together these considerations suggest that melatonin might be a therapeutical benefit in MS as well as in other diseases. However, as the authors of the Cell study also pointed out, extreme caution should be exercised because of possible cross-regulation of melatonin signaling. Further studies are, thus, clearly needed and especially well controlled clinical trials. Unfortunately, nowadays the vast majority of melantonin studies continue to deal with its anti-oxidant properties. Perhaps, this single-issue attitude depends on the fact that the immunological effects of melatonin are rather difficult to understand clearly. In fact, it has been widely reported that melatonin may both stimulate and suppress the immune response.
An interesting hypothesis aimed at explaining these opposite effects is that melatonin may be an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses Carrillo-Vico, A, 2013. In fact, on one side, melatonin may counteract secondary immmunodeficiency states and be of therapeutic value in models of viral and bacterial infections Maestroni G, 1999, Elmahallawy EK, et al., 2015, while on the other hand it was shown to prolong graft survival after organ transplantation in animals Fildes JE et al., 2009 .
Finally, I take the freedom to comment on the way the authors of the Cell study came across on melatonin. They were analyzing the seasonality of MS relapses looking primarily at sun exposure as a promoter of vitamin D synthesis that is known to have anti-inflammatory effects. However, the seasonality of vitamin D synthesis did not match that of MS relapses. Therefore they looked at the role of melatonin that was considered just one of the factors undergoing a seasonal variability.
In fact, by going through the paper it seems clear that the authors ignored most previous studies on the immunologic effects of melatonin. No referring to or discussion about this issue is present in the text, and in the references they quoted one general review about melatonin and a couple of papers reporting the presence of membrane and nuclear melatonin receptors on rodent and human immunocompetent cells. This is surprising inasmuch as, in my opinion, a discussion of the varied immunologic effects of melatonin, would have reinforced both the rationale and the conclusion of their investigation. Now, the fact that big international groups (the paper is authored by 15 authors belonging to 7 different affiliations) ignore previous work is becoming a common ethical issue, especially when the ‘rediscovered’ findings concern the neuroendocrine and immune crosstalk. Recently, it happened that a well-known research group ‘rediscovered’ that bone marrow functions may be affected by catecholamines. Their studies have been published in prestigious scientific journals but no quoting of any of the previous original findings demonstrating the same concept is present in any of their publications Cosentino M et al, 2015. Perhaps, this bibliographic negligence stems directly from the cultural separation from physiology that still affects many scientists who continue to conceive a living organism as the arithmetical sum of its organs Maestroni G, 2004.
Georges JM Maestroni – Section of Experimental and Clinical Pharmacology, Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy.