Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins α-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators.
Parkinson's disease (PD) is characterized by the presence of Lewy bodies and degeneration of dopaminergic neurons. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Lewy body component α-synuclein activates glia in PD pathogenesis. Mast cells and glia maturation factor (GMF) are implicated in neuroinflammatory conditions including Multiple Sclerosis. However, the role of mast cells in PD is not yet known. We have analyzed the effect of recombinant GMF, MPP+, α-synuclein and interleukin-33 (IL-33) on mouse bone marrow-derived cultured mast cells (BMMCs), human umbilical cord blood-derived cultured mast cells (hCBMCs) and mouse brain-derived cultured astrocytes by quantifying cytokines/chemokines released using ELISA or by detecting the expression of co-stimulatory molecules CD40 and CD40L by flow cytometry. GMF significantly released chemokine (C-C motif) ligand 2 (CCL2) from BMMCs but its release was reduced in BMMCs from GMF knockout mice. GMF, α-synuclein and MPP+ released IL-1β, β-hexosaminidase from BMMCs, and IL-8 from hCBMCs. GMF released CCL5, and IL-33- induced the expression of GMF from hCBMCs. Novel GMF expression was detected in hCBMCs and BMMCs by immunocytochemistry. GMF released tumor necrosis factor-alpha (TNF-α) from mouse astrocytes, and this release was greater in BMMC- astrocyte coculture than in individual cultures. Flow cytometry results showed increased IL-33 expression by GMF and MPP+, and GMF-induced CD40 expression in astrocytes. Proinflammatory mediator release by GMF, MPP+ and α-synuclein, as well as GMF expression by mast cells indicate a potential therapeutic target for neurodegenerative diseases including PD.
Veterans Affairs Health Care System, Iowa City, Iowa, United States of America; Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Duraisamy
D
Kempuraj
Veterans Affairs Health Care System, Iowa City, Iowa, United States of America; Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Ramasamy
R
Thangavel
Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Evert
E
Yang
Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Sagar
S
Pattani
Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Smita
S
Zaheer
Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Donna A
DA
Santillan
Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Mark K
MK
Santillan
Veterans Affairs Health Care System, Iowa City, Iowa, United States of America; Department of Neurology, Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Asgar
A
Zaheer
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020904:Glia Maturation Factor / Q000494:pharmacology*; D006801:Humans; D000067596:Interleukin-33 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D051844:alpha-Synuclein / Q000378:metabolism*
D019013:CD40 Antigens; D020904:Glia Maturation Factor; D000067596:Interleukin-33; D016209:Interleukin-8; D051844:alpha-Synuclein; D023201:CD40 Ligand; D015655:1-Methyl-4-phenylpyridinium