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Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

ABSTRACT: Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

SUBMITTER: Ostkamp P

PROVIDER: S-EPMC7817192 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Ostkamp Patrick P Salmen Anke A Pignolet Béatrice B Görlich Dennis D Andlauer Till F M TFM Schulte-Mecklenbeck Andreas A Gonzalez-Escamilla Gabriel G Bucciarelli Florence F Gennero Isabelle I Breuer Johanna J Antony Gisela G Schneider-Hohendorf Tilman T Mykicki Nadine N Bayas Antonios A Then Bergh Florian F Bittner Stefan S Hartung Hans-Peter HP Friese Manuel A MA Linker Ralf A RA Luessi Felix F Lehmann-Horn Klaus K Mühlau Mark M Paul Friedemann F Stangel Martin M Tackenberg Björn B Tumani Hayrettin H Warnke Clemens C Weber Frank F Wildemann Brigitte B Zettl Uwe K UK Ziemann Ulf U Müller-Myhsok Bertram B Kümpfel Tania T Klotz Luisa L Meuth Sven G SG Zipp Frauke F Hemmer Bernhard B Hohlfeld Reinhard R Brassat David D Gold Ralf R Gross Catharina C CC Lukas Carsten C Groppa Sergiu S Loser Karin K Wiendl Heinz H Schwab Nicholas N

Proceedings of the National Academy of Sciences of the United States of America 20210101 1

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), r ...[more]

PMID: 33376202

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Project description:Pharmaceutical agents currently approved for the treatment of multiple sclerosis reduce relapse rates, but do not reverse or prevent neurodegeneration nor initiate myelin repair. The highly selective estrogen receptor (ER) β ligand chloroindazole (IndCl) shows particular promise promoting both remyelination while reducing inflammatory cytokines in the central nervous system of mice with experimental autoimmune encephalomyelitis. To optimize these benefits, we developed and screened seven novel IndCl analogues for their efficacy in promoting primary oligodendrocyte (OL) progenitor cell survival, proliferation, and differentiation in vitro by immunohistochemistry. Two analogues, IndCl-o-chloro and IndCl-o-methyl, induced proliferation and differentiation equivalent to IndCl and were selected for subsequent in vivo evaluation for their impact on clinical disease course, white matter pathology, and inflammation. Both compounds ameliorated disease severity, increased mature OLs, and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord. These effects were accompanied by reduced production of the OL toxic molecules interferon-γ and chemokine (C-X-C motif) ligand, CXCL10 by splenocytes with no discernable effect on central nervous system-infiltrating leukocyte numbers, while IndCl-o-methyl also reduced peripheral interleukin (IL)-17. In addition, expression of the chemokine CXCL1, which is associated with developmental oligodendrogenesis, was upregulated by IndCl and both analogues. Furthermore, callosal compound action potential recordings from analogue-treated mice demonstrated a larger N1 component amplitude compared to vehicle, suggesting more functionally myelinated fibers. Thus, the o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases.

Dataset Information

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

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