The role of interleukin (IL)-2 cytokine family in Parkinson's disease

Abstract

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.