Wu Si-Ting, Zhang Tian-Xiang, Liu Zhirui, An Xueting, Du Xiaoshan, Yang Shu, Wu Ti, Di Guanju, Song Jingshi, Feng Bin, Wang Chunyang, Zhang Chao
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, China.
J Neuroinflammation. 2025 Jun 6;22(1):152. doi: 10.1186/s12974-025-03472-w.
Never in mitosis gene A (NIMA)-related kinase 2 (NEK2), a member of the serine-threonine kinase family, is critically involved in the regulation of the cell cycle. Upregulation of NEK2 is associated with aberrant B cell proliferation, a phenomenon potentially driven by NEK2-mediated disruption of the PKM1/PKM2 equilibrium. The overexpression of NEK2 in the B cell lineage may facilitate the maturation processes of B cells. Nonetheless, the precise role of NEK2 in modulating B cell-mediated immunity in autoimmune disorders remains to be fully elucidated. In this study, we demonstrate that NEK2 was significantly upregulated in multiple sclerosis (MS) patients. Pharmacological inhibition of NEK2 resulted in a marked reduction in the expression of co-stimulatory molecules CD80 and CD86 on B cells, concomitant with a suppression of their proliferation and differentiation into antibody-secreting cells (ASCs) and class-switched memory B cells (SWM). Administration of the NEK2 inhibitor INH1 in a murine model of experimental autoimmune encephalomyelitis (EAE) led to notable improvements in neurological function, amelioration of demyelination, and a decrease in the infiltration of inflammatory cells in the central nervous system (CNS) compared to vehicle-treated EAE mice. Mass cytometry analysis revealed that NEK2 inhibition downregulated the expression of co-stimulatory molecules and diminished the proportion of Th1 cells in the CD4 + T cell population. In vitro studies further substantiated that NEK2 blockade attenuated CD4 + T cell proliferation and differentiation into Th1 cells by disrupting B-T cell interactions. Collectively, these findings underscore an immunomodulatory function for NEK2 and highlight its potential as a therapeutic target in the treatment of multiple sclerosis.
丝氨酸 - 苏氨酸激酶家族成员有丝分裂相关基因A（NIMA）相关激酶2（NEK2），它在细胞周期调控中起关键作用。NEK2的上调与异常的B细胞增殖有关，这一现象可能由NEK2介导的PKM1/PKM2平衡破坏所驱动。NEK2在B细胞谱系中的过表达可能促进B细胞的成熟过程。然而，NEK2在自身免疫性疾病中调节B细胞介导的免疫的确切作用仍有待充分阐明。在本研究中，我们证明NEK2在多发性硬化症（MS）患者中显著上调。对NEK2进行药理抑制导致B细胞上共刺激分子CD80和CD86的表达显著降低，同时抑制了它们增殖并分化为抗体分泌细胞（ASC）和类别转换记忆B细胞（SWM）。在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中给予NEK2抑制剂INH1，与给予赋形剂的EAE小鼠相比，导致神经功能显著改善、脱髓鞘减轻以及中枢神经系统（CNS）中炎性细胞浸润减少。质谱流式细胞术分析显示，抑制NEK2可下调共刺激分子的表达，并减少CD4 + T细胞群体中Th1细胞的比例。体外研究进一步证实，阻断NEK2可通过破坏B - T细胞相互作用减弱CD4 + T细胞增殖并分化为Th1细胞。总的来说，这些发现强调了NEK2的免疫调节功能，并突出了其作为治疗多发性硬化症的治疗靶点的潜力。
