Kuo Ping-Chang, Zhao Zixuan, Scofield Barbara A, Paraiso Hallel C, Yu I-Chen Ivorine, Brown Dennis A, Yen Jui-Hung Jimmy
Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States.
Doctor of Medicine Program, Indiana University School of Medicine, Fort Wayne, IN, United States.
J Neuroimmunol. 2025 Apr 15;401:578557. doi: 10.1016/j.jneuroim.2025.578557. Epub 2025 Feb 17.
Multiple sclerosis (MS) is an autoimmune disorder and characterized by immune-mediated neuroinflammation and demyelination triggered by the CNS resident immune cells, microglia (MG), and CNS infiltrating pathogenic T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, and MG activation and pathogenic Th1/Th17 cell infiltration is responsible for EAE development and progression. We previously demonstrated that benzoylacetonitriles exerted neuro-immunomodulatory activity and identified compound 7a (referred to henceforth as BTA) as promising analog. Here, we investigated whether BTA possessed effects on modulating inflammatory responses in EAE and assessed its effects on MG activation and pathogenic Th1/Th17 differentiation and CNS infiltration in EAE. Our results showed BTA ameliorated disease severity in the chronic C57BL/6 EAE model. Further studies demonstrated BTA suppressed MG activation, attenuated CNS Th1/Th17 infiltration, and inhibited peripheral Th1/Th17 differentiation in EAE. Using protein array, we confirmed BTA inhibited MG activation by suppressing inflammatory cytokines/chemokine production. Furthermore, BTA suppressed Th1/Th17 polarization in vitro, indicating a direct suppressive effect of BTA on Th1/Th17 differentiation. Finally, our results showed that BTA prevented disease relapse in the relapsing-remitting SJL EAE model. In conclusion, our study demonstrates BTA possessed protective and therapeutic effects by ameliorating disease severity in the chronic EAE and mitigating relapse in the relapsing-remitting EAE, respectively. Further analysis revealed BTA exerted effects on inhibiting MG activation and Th1/Th17 differentiation, demonstrated by in vivo and in vitro studies. Altogether, our results suggest the benzoylacetonitrile scaffold could be developed as a novel therapeutic agent for MS/EAE treatment.
多发性硬化症（MS）是一种自身免疫性疾病，其特征是由中枢神经系统驻留免疫细胞小胶质细胞（MG）和中枢神经系统浸润的致病性T细胞引发的免疫介导的神经炎症和脱髓鞘。实验性自身免疫性脑脊髓炎（EAE）是MS的动物模型，MG激活和致病性Th1/Th17细胞浸润是EAE发生和发展的原因。我们之前证明苯甲酰乙腈具有神经免疫调节活性，并确定化合物7a（以下简称BTA）是一种有前景的类似物。在此，我们研究了BTA是否对EAE中的炎症反应具有调节作用，并评估了其对EAE中MG激活、致病性Th1/Th17分化和中枢神经系统浸润的影响。我们的结果表明，BTA改善了慢性C57BL/6 EAE模型中的疾病严重程度。进一步的研究表明，BTA抑制了MG激活，减轻了中枢神经系统Th1/Th17浸润，并抑制了EAE中外周Th1/Th17分化。使用蛋白质阵列，我们证实BTA通过抑制炎性细胞因子/趋化因子的产生来抑制MG激活。此外，BTA在体外抑制Th1/Th17极化，表明BTA对Th1/Th17分化具有直接抑制作用。最后，我们的结果表明，BTA预防了复发缓解型SJL EAE模型中的疾病复发。总之，我们的研究表明，BTA分别通过改善慢性EAE中的疾病严重程度和减轻复发缓解型EAE中的复发而具有保护和治疗作用。进一步分析表明，体内和体外研究均证明BTA对抑制MG激活和Th1/Th17分化有作用。总之，我们的结果表明苯甲酰乙腈支架可开发为治疗MS/EAE的新型治疗药物。
