Melatonin as an inducer of Th17 cell differentiation: new mechanisms

Cells of the immune system are sensitive to the action of melatonin, and the most obvious target of the hormone is the Th17 T helper subset: in addition to two high-affinity membrane receptors for melatonin, MT1 and MT2, these cells express a nuclear receptor, RORα. Among the secondary messengers involved in the transmission of signals from melatonin receptors, proteins of the sirtuin family are currently of particular interest. It is known that in non-tumor cells, sirtuin 1 (SIRT1) not only increases its expression in response to melatonin, but is also involved in the implementation of melatonin effects, as indicated by inhibitory assays using a specific SIRT1 blocker or corresponding siRNA/shRNA. This relates to the regulation of circadian oscillators, as well as the anti-inflammatory, antioxidant and anti-apoptotic effects of melatonin. Further mechanisms of SIRT1 activity in the cell include transcriptional and posttranscriptional regulation of gene expression through deacetylation of histones and non-histone proteins, and the apparent target of SIRT1 is the transcription factor RORα. It is this factor that mediates classical melatonin/SIRT1-dependent transcriptional control of key circadian regulators, the genes of which have ROR-binding sequences in their promoters. These data raise questions about the functions of SIRT1 in other cells expressing RORα, in particular in Th17 T helper cells, for which it is one of two key differentiation factors, along with RORγt. And if for RORα such a connection still remains hypothetical, for RORγt it has been convincingly demonstrated in studies both in vivo and in vitro: it has been shown that SIRT1 directly binds to RORγt and stimulates the development of Th17 cells, and blockade of sirtuin suppresses the differentiation of these cells in normal and prevents the development of Th17-associated pathology in mice. Summarizing these data, we can confidently predict the existence of a new mechanism for the regulation of the T helper Th17 population by melatonin, through the activation of sirtuin SIRT1, and this mechanism must be taken into account when interpreting data on the immunoregulatory activity of melatonin.