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

Wang, Tongguang; Allie, Rameeza; Conant, Katherine; Haughey, Norman J.; Turchan–Cholewo, Jadwiga; Hahn, Katrin; Rosen, Antony; Steiner, Joseph P.; Keswani, Sanjay C.; Jones, M. D.; Calabresi, Peter A.; Nath, Avindra

doi:10.1096/fj.05-5022fje

Cited by 59 publications

(61 citation statements)

References 50 publications

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“…In the central nervous system, GzmB cleaves a glutamate receptor (GluR3), potentially contributing to immunoneurotoxicity, excitation, and autoimmunity in the brain (199,200). GzmB on its own causes death of neurons in a pertussis toxin-sensitive manner, suggesting possible cleavage or involvement of G protein-coupled receptors (201). Other potential GzmB receptor targets are Notch1 and FGFR1, which may inhibit growth signals to developing or malignant cells (202).…”

Section: Extracellular Roles Of Granzymesmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

538

552

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The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

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Section: Extracellular Roles Of Granzymesmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

538

552

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“…Indeed, T cells activated by a soluble anti-CD3 Ab induced severe neurotoxic effect in both allogeneic and syngeneic systems in vitro (22); however, the mechanisms of this T cell-mediated neurotoxicity have not been explored. It has recently been shown that recombinant GrB induces neuronal injury in vitro (23). However, recombinant GrB does not have the posttranslational changes occurring in the granule-derived GrB that are required to enter the target cell (24).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Granule-Derived Granzyme B Mediates the Vulnerability of Human Neurons to T Cell-Induced Neurotoxicity

Haile

Simmen

Pasichnyk

et al. 2011

The Journal of Immunology

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Multiple sclerosis (MS) is considered an autoimmune disease of the CNS and is characterized by inflammatory cells infiltrating the CNS and inducing demyelination, axonal loss, and neuronal death. Recent evidence strongly suggests that axonal and neuronal degeneration underlie the progression of permanent disability in MS. In this study, we report that human neurons are selectively susceptible to the serine-protease granzyme B (GrB) isolated from cytotoxic T cell granules. In vitro, purified human GrB induced neuronal death to the same extent as the whole activated T cell population. On the contrary, activated T cells isolated from GrB knockout mice failed to induce neuronal injury. We found that following internalization through various parts of neurons, GrB accumulated in the neuronal soma. Within the cell body, GrB diffused out of endosomes possibly through a perforin-independent mechanism and induced subsequent activation of caspases and cleavage of α-tubulin. Inhibition of caspase-3, a well-known substrate for GrB, significantly reduced GrB-mediated neurotoxicity. We demonstrated that treatment of neurons with mannose-6-phosphate prevented GrB entry and inhibited GrB-mediated neuronal death, suggesting mannose-6-phosphate receptor-dependent endocytosis. Together, our data unveil a novel mechanism by which GrB induces selective neuronal injury and suggest potential new targets for the treatment of inflammatory-mediated neurodegeneration in diseases such as MS.

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“…However, in resistant mouse strains (C57Bl/6), the infection is cleared within 3 weeks by a strong anti-viral CD8 T cells response that controls viral spread by both lytic and non-lytic mechanisms. Effector CD8 T cells can use these mechanisms to target resident CNS cells [9,54,55].…”

Section: Cd8 T Cells In Animal Models Of Msmentioning

confidence: 99%

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

et al. 2011

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a b s t r a c tMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS.

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

Cited by 59 publications

References 50 publications

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Granule-Derived Granzyme B Mediates the Vulnerability of Human Neurons to T Cell-Induced Neurotoxicity

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

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