Granzyme B mediates neurotoxicity through a G-protein-coupled receptor

Tongguang Wang, Rameeza Allie, Katherine Conant, Norman Haughey, Jadwiga Turchan-Chelowo, Katrin Hahn, Antony Rosen, Joseph Steiner, Sanjay Keswani, Melina Jones, Peter Calabresi, Avindra Nath

Research output: Contribution to journalArticle

Abstract

Neuroinflammatory diseases such as multiple sclerosis (MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Giα protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be markedly potentiated by stromal-derived factor 1α. GrB-induced neurotoxicity could also be blocked by vitamin E and a neuroimmunophilin ligand. In conclusion, GrB may be an important mediator of neuronal injury in T cell-mediated neuroinflammatory disorders.

Original languageEnglish (US)
JournalFASEB Journal
Volume20
Issue number8
DOIs
StatePublished - Jun 2006

Fingerprint

Granzymes
neurotoxicity
G-Protein-Coupled Receptors
T-cells
T-lymphocytes
T-Lymphocytes
Toxicity
toxicity
neurons
Neurons
calcium
pertussis toxin
astrocytes
Calcium
caspases
sclerosis
Perforin
mannose
Pertussis Toxin
Wounds and Injuries

Keywords

  • cAMP
  • Caspase-3
  • Immune reconstitution syndrome
  • Multiple sclerosis
  • Pertussis toxin
  • T cell

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Wang, T., Allie, R., Conant, K., Haughey, N., Turchan-Chelowo, J., Hahn, K., ... Nath, A. (2006). Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. FASEB Journal, 20(8). https://doi.org/10.1096/fj.05-5022fje

Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. / Wang, Tongguang; Allie, Rameeza; Conant, Katherine; Haughey, Norman; Turchan-Chelowo, Jadwiga; Hahn, Katrin; Rosen, Antony; Steiner, Joseph; Keswani, Sanjay; Jones, Melina; Calabresi, Peter; Nath, Avindra.

In: FASEB Journal, Vol. 20, No. 8, 06.2006.

Research output: Contribution to journalArticle

Wang, T, Allie, R, Conant, K, Haughey, N, Turchan-Chelowo, J, Hahn, K, Rosen, A, Steiner, J, Keswani, S, Jones, M, Calabresi, P & Nath, A 2006, 'Granzyme B mediates neurotoxicity through a G-protein-coupled receptor', FASEB Journal, vol. 20, no. 8. https://doi.org/10.1096/fj.05-5022fje
Wang, Tongguang ; Allie, Rameeza ; Conant, Katherine ; Haughey, Norman ; Turchan-Chelowo, Jadwiga ; Hahn, Katrin ; Rosen, Antony ; Steiner, Joseph ; Keswani, Sanjay ; Jones, Melina ; Calabresi, Peter ; Nath, Avindra. / Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. In: FASEB Journal. 2006 ; Vol. 20, No. 8.
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