Ribeiro Ana Rita, Pereira Raquel, Barros Catarina, Barateiro Andreia, Alberro Ainhoa, Basto Afonso P, Graça Luís, Pinto Maria Vaz, Santos Fábio M F, Gois Pedro M P, Howlett Susan E, Fernandes Adelaide
Faculdade de Farmácia, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal.
Departamento de Ciências Farmacêuticas E Do Medicamento, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal.
J Neuroimmune Pharmacol. 2025 Apr 14;20(1):37. doi: 10.1007/s11481-025-10195-5.
Multiple Sclerosis (MS) is the leading inflammatory and non-traumatic cause of disability in young adults, with late-onset MS emerging in middle-aged patients often resulting in poorer treatment responses and worse prognoses. The calcium-binding protein S100B is elevated in MS patients, and its targeting has shown promise in reducing disease severity in experimental autoimmune encephalomyelitis (EAE) models. However, most studies on MS pathology have focused on young animal models, leaving a gap in understanding the effects of age and S100B ablation on disease progression throughout the lifespan. This study aimed to characterize EAE in mice of different ages, examining demyelination, inflammation, and immune responses to determine whether S100B ablation could mitigate MS pathogenesis across the lifespan. EAE was induced in six cohorts of C57BL/6 mice: young adults (3 months), older adults (6 months), and middle-aged (12 months), including corresponding S100B knockout (KO) groups, followed for 23 days. Upon sacrifice, spinal cords were assessed via immunohistochemistry and Real-Time qPCR, while splenocytes were analyzed for immune cell characterization. Results indicated a more severe disease course in 12-month-old mice, marked by increased gliosis, inflammation, and impaired microglial phagocytic activity. Notably, S100B absence reduced gliosis and inflammatory markers across all ages, with 12-month-old S100B KO mice showing increased regulatory T cells. These findings highlight the exacerbating role of age and elevated S100B in MS progression, underscoring the importance of identifying age-specific MS markers and therapeutic targets.
多发性硬化症（MS）是年轻成年人中导致残疾的主要炎症性和非创伤性病因，中年患者中出现的迟发性MS往往导致较差的治疗反应和预后。钙结合蛋白S100B在MS患者中升高，其靶向治疗已显示出在实验性自身免疫性脑脊髓炎（EAE）模型中降低疾病严重程度的前景。然而，大多数关于MS病理学的研究都集中在年轻动物模型上，在理解年龄和S100B缺失对整个生命周期疾病进展的影响方面存在差距。本研究旨在表征不同年龄小鼠的EAE，检查脱髓鞘、炎症和免疫反应，以确定S100B缺失是否可以在整个生命周期中减轻MS发病机制。在六组C57BL/6小鼠中诱导EAE：年轻成年小鼠（3个月）、成年老年小鼠（6个月）和中年小鼠（12个月），包括相应的S100B基因敲除（KO）组，持续观察23天。处死后，通过免疫组织化学和实时定量PCR评估脊髓，同时分析脾细胞以进行免疫细胞表征。结果表明，12个月大的小鼠病程更严重，表现为胶质增生增加、炎症和小胶质细胞吞噬活性受损。值得注意的是，S100B缺失降低了所有年龄段的胶质增生和炎症标志物，12个月大的S100B基因敲除小鼠显示调节性T细胞增加。这些发现突出了年龄和升高的S100B在MS进展中的加剧作用，强调了识别年龄特异性MS标志物和治疗靶点的重要性。
