NEK2调节B细胞功能和实验性自身免疫性脑脊髓炎的严重程度。

IF 10.1 1区 医学 Q1 IMMUNOLOGY
Si-Ting Wu, Tian-Xiang Zhang, Zhirui Liu, Xueting An, Xiaoshan Du, Shu Yang, Ti Wu, Guanju Di, Jingshi Song, Bin Feng, Chunyang Wang, Chao Zhang
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引用次数: 0

摘要

有丝分裂基因A (NIMA)相关激酶2 (NEK2)是丝氨酸-苏氨酸激酶家族的一员,在细胞周期的调控中起关键作用。NEK2的上调与B细胞增殖异常有关,这一现象可能是由NEK2介导的PKM1/PKM2平衡的破坏所驱动的。NEK2在B细胞谱系中的过表达可能促进B细胞的成熟过程。尽管如此,NEK2在自身免疫性疾病中调节B细胞介导的免疫中的确切作用仍有待充分阐明。在这项研究中,我们证明了NEK2在多发性硬化症(MS)患者中显著上调。NEK2的药理抑制导致B细胞上共刺激分子CD80和CD86的表达显著降低,同时抑制它们向抗体分泌细胞(ASCs)和类别转换记忆B细胞(SWM)的增殖和分化。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可显著改善神经功能,改善脱髓鞘,并减少中枢神经系统(CNS)中炎症细胞的浸润。大量细胞分析显示,NEK2抑制下调了共刺激分子的表达,降低了Th1细胞在CD4 + T细胞群中的比例。体外研究进一步证实,NEK2阻断通过破坏B-T细胞相互作用减弱CD4 + T细胞的增殖和向Th1细胞的分化。总的来说,这些发现强调了NEK2的免疫调节功能,并强调了其作为多发性硬化症治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NEK2 regulates B cell function and the severity of experimental autoimmune encephalomyelitis.

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.

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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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