Granzyme B-induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel

Increasing evidence supports a critical role of T cells in neurodegeneration associated with acute and subacute brain inflammatory disorders. Granzyme B (GrB), released by activated T cells, is a cytotoxic proteinase which may induce perforin-independent neurotoxicity. Here, we studied the mechanism...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2012-08, Vol.7 (8), p.e43950
Main Authors: Wang, Tongguang, Lee, Myoung-Hwa, Choi, Elliot, Pardo-Villamizar, Carlos A, Lee, Sung Bin, Yang, In Hong, Calabresi, Peter A, Nath, Avindra
Format: Article
Language:English
Subjects:
Activation
Animals
Apoptosis
Biocompatibility
Biology
Biomedical engineering
Brain
Brain research
Brain-derived neurotrophic factor
Care and treatment
Cell Count
Cell surface
Cerebral cortex
Clofazimine
Clofazimine - pharmacology
Cyclic AMP
Cytotoxicity
Disorders
Dosage and administration
Female
Gene Expression Regulation - drug effects
Granzyme B
Granzymes - toxicity
Humans
Infections
Inflammatory diseases
Kinases
Kv1.3 Potassium Channel - metabolism
Lesions
Lymphocytes
Lymphocytes T
Medicine
Multiple sclerosis
Multiple Sclerosis - metabolism
Multiple Sclerosis - pathology
Nervous system
Neurites - drug effects
Neurites - metabolism
Neurodegeneration
Neurology
Neurons
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neurotoxicity
Neurotoxicity syndromes
Neurotoxins - toxicity
Notch1 protein
Perforin
Pharmacology
Phosphorylation
Potassium
Potassium channels (voltage-gated)
Protease inhibitors
Proteinase
Proteinase-activated receptor 1
Proteins
Proteolysis - drug effects
Rats
Rats, Sprague-Dawley
Receptor, Notch1 - metabolism
Receptor, PAR-1 - metabolism
Rodents
siRNA
T cells
Toxicity
Translocation
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Increasing evidence supports a critical role of T cells in neurodegeneration associated with acute and subacute brain inflammatory disorders. Granzyme B (GrB), released by activated T cells, is a cytotoxic proteinase which may induce perforin-independent neurotoxicity. Here, we studied the mechanism of perforin-independent GrB toxicity by treating primary cultured human neuronal cells with recombinant GrB. GrBactivated the protease-activated receptor (PAR)-1 receptor on the neuronal cell surface leading to decreased intracellular cyclic AMP levels. This was followed by increased expression and translocation of the voltage gated potassium channel, Kv1.3 to the neuronal cell membrane. Similar expression of Kv1.3 was also seen in neurons of the cerebral cortex adjacent to active inflammatory lesions in patients with multiple sclerosis. Kv1.3 expression was followed by activation of Notch-1 resulting in neurotoxicity. Blocking PAR-1, Kv1.3 or Notch-1 activation using specific pharmacological inhibitors or siRNAs prevented GrB-induced neurotoxicity. Furthermore, clofazimine protected against GrB-induced neurotoxicity in rat hippocampus, in vivo. These observations indicate that GrB released from T cells induced neurotoxicity by interacting with the membrane bound Gi-coupled PAR-1 receptor and subsequently activated Kv1.3 and Notch-1. These pathways provide novel targets to treat T cell-mediated neuroinflammatory disorders. Kv1.3 is of particular interest since it is expressed on the cell surface, only under pathological circumstances, and early in the cascade of events making it an attractive therapeutic target.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0043950