Bee Venom Phospholipase A2, a Novel Foxp3+ Regulatory T Cell Inducer, Protects Dopaminergic Neurons by Modulating Neuroinflammatory Responses in a Mouse Model of Parkinson's Disease

Foxp3-expressing CD4(+) regulatory T cells (Tregs) are vital for maintaining immune tolerance in animal models of various immune diseases. In the present study, we demonstrated that bee venom phospholipase A(2) (bvPLA(2)) is the major BV compound capable of inducing Treg expansion and promotes the survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. We associated this neuroprotective effect of bvPLA(2) with microglial deactivation and reduction of CD4(+) T cell infiltration. Interestingly, bvPLA(2) had no effect on mice depleted of Tregs by injecting anti-CD25 Ab. This finding indicated that Treg-mediated modulation of peripheral immune tolerance is strongly involved in the neuroprotective effects of bvPLA(2). Furthermore, our results showed that bvPLA(2) directly bound to CD206 on dendritic cells and consequently promoted the secretion of PGE(2), which resulted in Treg differentiation via PGE(2) (EP2) receptor signaling in Foxp3(-)CD4(+) T cells. These observations suggest that bvPLA(2)-CD206-PGE(2)-EP2 signaling promotes immune tolerance through Treg differentiation and contributes to the prevention of various neurodegenerative diseases, including Parkinson's disease.