Editors' ChoiceImmunology

Remission by melatonin

Sci. Signal.  29 Sep 2015:
Vol. 8, Issue 396, pp. ec276
DOI: 10.1126/scisignal.aad5266

Multiple sclerosis (MS) is a demyelinating, inflammatory autoimmune disease of the central nervous system (CNS) that in some patients cycles through periods of relapse and remission. Farez et al. found that effects on immune cells mediated by circadian changes in circulating melatonin abundance may explain the tendency of MS to relapse in the summer (see also Lee and Cua). In a cohort of relapse-remitting MS patients, the incidence of relapse was lowest in the winter when serum melatonin concentration was highest. The serum concentration of melatonin positively correlated with the anti-inflammatory cytokine IL-10, which is produced by type 1 regulatory (Tr1) cells, and negatively correlated with the proinflammatory cytokine IL-17, which is produced by T helper 17 (TH17) cells. Adding melatonin or the melatonin receptor agonist agomelatine to cultured human or murine CD4+ T cells suppressed their expression of IL17 and differentiation into TH17 cells, whereas it promoted their expression of IL10 and differentiation into Tr1 cells when cultured in the respective polarizing conditions. In a mouse model of MS, melatonin administration suppressed autoimmune encephalitis and decreased the number of TH17 cells, whereas it increased the number of IL-10–secreting T cells found in the spleen, lymph nodes, and CNS. Manipulating the abundance or activity of various melatonin signaling pathway components in cultured T cells or in mice revealed that melatonin, through binding to its receptor MTNR1A, activated the kinases ERK1 and ERK2 and the transcriptional repressor NFIL3 in T cells, which together suppressed the transcriptional activity that favors TH17 cell differentiation and promoted that which favors Tr1 cell differentiation. These findings suggest that melatonin supplementation—particularly in the summer when MS patients’ natural melatonin concentrations are lowest—might be combined with therapies targeting TH17 cells to more effectively suppress inflammation.

M. F. Farez, I. D. Mascanfroni, S. P. Méndez-Huergo, A. Yeste, G. Murugaiyan, L. P. Garo, M. E. Balbuena Aguirre, B. Patel, M. C. Ysrraelit, C. Zhu, V. K. Kuchroo, G. A. Rabinovich, F. J. Quintana, J. Correale, Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162, 1338–1352 (2015). [PubMed]

J. S. Lee, D. J. Cua, Melatonin lulling Th17 cells to sleep. Cell 162, 1212–1214 (2015). [PubMed]

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