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

Abstract

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 A2 (bvPLA2) 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 bvPLA2 with microglial deactivation and reduction of CD4+ T cell infiltration. Interestingly, bvPLA2 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 bvPLA2. Furthermore, our results showed that bvPLA2 directly bound to CD206 on dendritic cells and consequently promoted the secretion of PGE2, which resulted in Treg differentiation via PGE2 (EP2) receptor signaling in Foxp3−CD4+ T cells. These observations suggest that bvPLA2-CD206-PGE2-EP2 signaling promotes immune tolerance through Treg differentiation and contributes to the prevention of various neurodegenerative diseases, including Parkinson’s disease.

Protective Effects of Intratracheally-Administered Bee Venom Phospholipase A2 on Ovalbumin-Induced Allergic Asthma in Mice

“…Our previous studies reported that bee venom treatment successfully protects various immune disorders by increasing Treg populations [9,26]. Furthermore, we found that PLA2 is the active compound in bee venom capable for modulating the Treg populations, both in vitro and in vivo [9,10,11].…”

“…Furthermore, we found that PLA2 is the active compound in bee venom capable for modulating the Treg populations, both in vitro and in vivo [9,10,11]. PLA2 from bee venom belongs to group III secreted PLA2 (sPLA2) enzymes, which play important roles in a wide range of cellular functions, including phospholipid metabolism, signal transduction, and inflammatory and immune responses [27].…”

“…PLA2 from bee venom belongs to group III secreted PLA2 (sPLA2) enzymes, which play important roles in a wide range of cellular functions, including phospholipid metabolism, signal transduction, and inflammatory and immune responses [27]. Chung et al have reported that bvPLA2 directly bound to CD206 mannose receptor on dendritic cells and induces the secretion of prostaglandin E2 (PGE2), which promotes immune tolerance through Treg differentiation via PGE2 receptor signaling and prevents the neuroinflammatory responses in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease [9]. In addition, anti-inflammatory effects bvPLA2 was also mediated by IL-10 secretion and Treg activation in cisplatin-induced acute kidney injury model [10].…”

“…However, bvPLA2 treatment suppressed the increment, suggesting that bvPLA2 can regulate the PLA2-mediated metabolic pathway in the lung. Moreover, other groups and we have tested whether enzymatic activity of bvPLA2 is necessary for its therapeutic effect using heat- or chemically-inactivated bvPLA2, and found that enzymatic activity of bvPLA2 is necessary [8,9,10]. Further studies to elucidate targets of this bee venom-derived enzyme for inhibiting lung inflammation are needed.…”

“…Bee venom PLA2 (bvPLA2) is one of the major components of bee venom [8]. Our previous studies reported that bvPLA2 directly bound to the CD206 mannose receptor, which promoted immune tolerance through Treg cells modulation and prevented various inflammatory responses, such as neuroinflammation, airway inflammation, and acute kidney injury [9,10,11]. To study the impact of the route of administration on bvPLA2 penetration into the lungs, bvPLA2 was delivered by intratracheal instillation in an OVA-challenged allergic airway inflammation mouse model.…”