Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model.

Autor: Konieczna-Wolska K; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Tri-City Central Animal Laboratory Research and Service Center, Medical University of Gdańsk, Gdańsk, Poland., Caratis F; Department of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland; Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland., Opiełka M; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland., Biernacki K; Department of Organic Chemistry, Gdańsk University of Technology, Gdańsk, Poland., Urbanowicz K; Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland., Klimaszewska J; Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland., Pobiarzyn P; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland., Krajewski O; Department of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland., Demkowicz S; Department of Organic Chemistry, Gdańsk University of Technology, Gdańsk, Poland., Smoleński RT; Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland., Karaszewski B; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Department of Adult Neurology, Medical University of Gdańsk and University Clinical Center, Gdańsk, Poland., Seuwen K; Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Rutkowska A; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Department of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland. Electronic address: ola.rutkowska@gumed.edu.pl.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Dec; Vol. 181, pp. 117653. Date of Electronic Publication: 2024 Nov 02.
DOI: 10.1016/j.biopha.2024.117653
Abstrakt: Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF 3 -7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF 3 -7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aleksandra Rutkowska has patent #EP24191137.9 pending to n/a. Bartosz Karaszewski has patent #EP24191137.9 pending to n/a. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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