Goleij Pouya, Amini Alireza, Tabari Mohammad Amin Khazeei, Hadipour Mahboube, Sanaye Pantea Majma, Alsharif Khalaf F, Daglia Maria, Larsen Danaé S, Khan Haroon
USERN Office, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran; Department of Genetics, Faculty of Biology, Sana Institute of Higher Education, Sari 4816118761, Iran.
Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Mazandaran 4815733971, Iran.
Cytokine. 2025 Jul;191:156954. doi: 10.1016/j.cyto.2025.156954. Epub 2025 May 2.
Parkinson's disease (PD) is a neurodegenerative disorder, which primarily impacts the nervous system, marked by its immune and inflammatory characteristics. The interleukin-2 (IL-2) cytokine family has a crucial role in regulating both neuroinflammation and immune activity, positioning it as one of the critical immune pathways in PD. Balancing pro-inflammatory and anti-inflammatory signals in PD heavily depends on the IL-2 cytokine family, that includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. This balance is vital for neuron survival and resistance to degeneration. Disruptions in IL-2 signaling can upset the equilibrium among regulatory T cells (Tregs) and pro-inflammatory T cells, such as Th1 and Th17, further aggravating the chronic neuroinflammation typical of PD. In PD, a decline in IL-2 or receptor dysfunction can hinder Treg activity, leading to increased inflammation and neurodegeneration. Similarly, IL-15 and IL-21 supports cytotoxic immune cell function, including natural killer (NK) cells and CD8+ T cells, which may exacerbate neuronal damage by sustaining pro-inflammatory processes. Moreover, IL-4 and IL-7 have anti-inflammatory roles in maintaining T cell homeostasis, and their dysregulation can contribute to interruption of the blood-brain barrier and increased infiltration of immune cells into the central nervous system. Targeting the IL-2 cytokine family in Parkinson's disease has shown therapeutic potential by expanding Tregs, which reduce neuroinflammation and promote dopaminergic neuron survival. Recombinant IL-2 and IL-2/anti-IL-2 complexes have demonstrated efficacy in animal models, enhancing Treg function and leading to improved neuroprotection. Additionally, IL-4-based therapies have been explored for their ability to shift microglia toward a neuroprotective phenotype, further enhancing neuronal survival by modulating inflammatory responses and cellular metabolism. Current research is exploring how to optimize cytokine delivery while minimizing immune side effects, with the goal of developing more targeted therapies for PD.
帕金森病（PD）是一种神经退行性疾病，主要影响神经系统，具有免疫和炎症特征。白细胞介素-2（IL-2）细胞因子家族在调节神经炎症和免疫活动中起关键作用，使其成为帕金森病关键的免疫途径之一。在帕金森病中，平衡促炎和抗炎信号严重依赖于IL-2细胞因子家族，该家族包括IL-2、IL-4、IL-7、IL-9、IL-15和IL-21。这种平衡对于神经元存活和抗变性至关重要。IL-2信号传导的破坏会扰乱调节性T细胞（Tregs）和促炎性T细胞（如Th1和Th17）之间的平衡，进一步加重帕金森病典型的慢性神经炎症。在帕金森病中，IL-2水平下降或受体功能障碍会阻碍Treg活性，导致炎症增加和神经变性。同样，IL-15和IL-21支持细胞毒性免疫细胞功能，包括自然杀伤（NK）细胞和CD8 + T细胞，它们可能通过维持促炎过程加剧神经元损伤。此外，IL-4和IL-7在维持T细胞稳态方面具有抗炎作用，它们的失调可能导致血脑屏障中断和免疫细胞向中枢神经系统的浸润增加。在帕金森病中靶向IL-2细胞因子家族已显示出治疗潜力，可通过扩增Tregs来减少神经炎症并促进多巴胺能神经元存活。重组IL-2和IL-2/抗IL-2复合物在动物模型中已证明有效，可增强Treg功能并导致更好的神经保护。此外，基于IL-4的疗法已因其将小胶质细胞转变为神经保护表型的能力而被探索，通过调节炎症反应和细胞代谢进一步提高神经元存活率。目前的研究正在探索如何优化细胞因子递送，同时将免疫副作用降至最低，目标是开发更有针对性的帕金森病治疗方法。
