T cell independent mechanism for copolymer-1-induced neuroprotection.
Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include bystander suppression of autoimmune T cells and attenuation of microglial responses. In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress. This neuroprotection is mediated through protein kinase Calpha and brain-derived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection. These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue.
Liu
Jianuo
J
Laboratory of Neuro-Immune Regulation, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Johnson
Thomas V
TV
Lin
Jamie
J
Ramirez
Servio H
SH
Bronich
Tatiana K
TK
Caplan
Steve
S
Persidsky
Yuri
Y
Gendelman
Howard E
HE
Kipnis
Jonathan
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D005455:Fluorescent Antibody Technique; D000068717:Glatiramer Acetate; D006801:Humans; D020287:In Situ Nick-End Labeling; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000187:drug effects / Q000276:immunology / Q000601:surgery; D010455:Peptides / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011923:Rats, Nude; D019311:Staurosporine / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010455:Peptides; D000068717:Glatiramer Acetate; D051571:Protein Kinase C-alpha; D019311:Staurosporine