Konieczna-Wolska Klaudia, Caratis Fionä, Opiełka Mikołaj, Biernacki Karol, Urbanowicz Krzysztof, Klimaszewska Joanna, Pobiarzyn Piotr, Krajewski Oliwier, Demkowicz Sebastian, Smoleński Ryszard T, Karaszewski Bartosz, Seuwen Klaus, Rutkowska Aleksandra
Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Tri-City Central Animal Laboratory Research and Service Center, Medical University of Gdańsk, Gdańsk, Poland.
Department of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland; Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland.
Biomed Pharmacother. 2024 Dec;181:117653. doi: 10.1016/j.biopha.2024.117653. Epub 2024 Nov 2.
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-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-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.
研究表明EBI2受体在髓鞘再生中发挥作用，表明其缺乏或拮抗会抑制这一过程。然而，用其内源性配体氧化甾醇7α,25-二羟基胆固醇（7α,25OHC）激活EBI2，并不会使髓鞘再生增强至超过自发髓鞘再生组织中观察到的水平。我们推测天然配体的短半衰期可能解释了这种缺乏有益效果的情况，并在铜螯合剂模型中测试了一种合成类似物CF-7α,25OHC。数据显示，延长7α,25OHC的生物利用度足以在体内加速髓鞘再生。此外，与内源性配体相比，该类似物上调了小鼠胼胝体中Ebi2的脑表达以及15种脂质的合成。从机制上讲，氧化甾醇浓度的增加可能破坏了其在脑脱髓鞘区域的梯度，导致表达EBI2的浸润免疫细胞分散，而不是在脱髓鞘区域积累。值得注意的是，类似物CF-7α,25OHC显著降低了淋巴细胞和单核细胞计数，模拟了一些治疗多发性硬化症最有效的疾病修饰疗法的关键作用机制。此外，与载体处理的小鼠相比，小脑中小鼠的Cd4+转录本和胼胝体中的CD4+细胞数量减少。这些发现提示了一种机制，通过该机制EBI2/7α,25OHC信号传导调节免疫反应并在体内加速髓鞘再生。
