title: 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.
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Chung
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Gihyun
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Chanju
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Minsook
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Hwan-suck
authors.initials: HS
authors.lastname: Chung
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea;
authors.forename: Hyunseong
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biology, University of California Riverside, Riverside, CA 92521; and.
authors.forename: Sung-joo S
authors.initials: SJ
authors.lastname: Bae
authors.affiliation: Department of Obstetrics and Gynecology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Deok-Sang
authors.initials: DS
authors.lastname: Hwang
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; hbae@khu.ac.kr.
authors.forename: Hyunsu
authors.identifier: http://orcid.org/0000-0002-0299-3582
authors.initials: H
authors.lastname: Bae
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology*; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D019476:Insect Proteins / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D020267:MPTP Poisoning / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D001514:Bee Venoms; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019476:Insect Proteins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D018696:Neuroprotective Agents; D011956:Receptors, Cell Surface; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054467:Phospholipases A2; D015232:Dinoprostone