Anti‐inflammatory effects of melatonin in multiple sclerosis

Abstract

Melatonin is a hormone with complex roles in the pathogenesis of autoimmune disorders. Over the years, it has become clear that melatonin may exacerbate some autoimmune conditions, whereas it alleviates others such as multiple sclerosis. Multiple sclerosis is an autoimmune disorder characterized by a dysregulated immune response directed against the central nervous system. Indeed, the balance between pathogenic CD4(+) T cells secreting IFN-γ (TH 1) or IL-17 (TH 17); and FoxP3(+) regulatory T cells and IL-10(+) type 1 regulatory T cells (Tr1 cells) is thought to play an important role in disease activity. Recent evidence suggests that melatonin ameliorates multiple sclerosis by controlling the balance between effector and regulatory cells, suggesting that melatonin-triggered signaling pathways are potential targets for therapeutic intervention. Here, we review the available data on the effects of melatonin on immune processes relevant for MS and discuss its therapeutic potential.

RORα is not a receptor for melatonin (response to DOI 10.1002/bies.201600018)

“…These include immunomodulatory and beneficial effects in a devastating disease, multiple sclerosis (MS), as was nicely discussed by Farez et al [3]. As much we agree with the majority of opinions in that paper, we are obliged to correct the cited theory on melatonin acting as a ligand for RORα or RORγ [3]. …”

“…Melatonin and its various metabolites exhibit many diverse pleiotropic activities triggered by receptor dependent and independent signaling pathways [2]. These include immunomodulatory and beneficial effects in a devastating disease, multiple sclerosis (MS), as was nicely discussed by Farez et al [3]. As much we agree with the majority of opinions in that paper, we are obliged to correct the cited theory on melatonin acting as a ligand for RORα or RORγ [3].…”

“…The challenge is how to explain the amplifying effects of melatonin on transcriptional activities that are downstream of RORα, as discussed in [3,5]. We believe that these events may be induced through indirect mechanisms of action (Fig.…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…MT 1 has a somewhat higher affinity to melatonin (pK i ≈ 9.48‐10.85) than MT 2 (pK i ≈9.60‐9.95), according to determinations summarized elsewhere . Although it has been shown that melatonin does not directly activate RORα, melatonin seems to indirectly affect transcriptional activities that are downstream of RORα . There is convincing evidence that macrophages express melatonin membrane receptors and also the possibly melatonin‐regulated RORα .…”

Melatonin protects bone marrow mesenchymal stem cells against iron overload‐induced aberrant differentiation and senescence

“…The pineal gland hormone melatonin ( N ‐acetyl‐5‐methoxytryptamine) has been shown to play an important role in many physiological processes, including controlling sleep‐wake rhythms, regulation of circadian cycle, cardiovascular function, immune defense, renal function, detoxification, as well as bone metabolism . In addition to these functions, numerous studies also demonstrated that melatonin can serve as one of the most powerful endogenous antioxidant agents by direct and indirect ways .…”