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Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia

Microglia are resident brain macrophages, which can cause neuronal loss when activated in infectious, ischemic, traumatic, and neurodegenerative diseases. Caspase-8 has both prodeath and prosurvival roles, mediating apoptosis and/or preventing RIPK1-mediated necroptosis depending on cell type and st...

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Autores principales: Fricker, Michael, Vilalta, Anna, Tolkovsky, Aviva M., Brown, Guy C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610987/
https://www.ncbi.nlm.nih.gov/pubmed/23386613
http://dx.doi.org/10.1074/jbc.M112.427880
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author Fricker, Michael
Vilalta, Anna
Tolkovsky, Aviva M.
Brown, Guy C.
author_facet Fricker, Michael
Vilalta, Anna
Tolkovsky, Aviva M.
Brown, Guy C.
author_sort Fricker, Michael
collection PubMed
description Microglia are resident brain macrophages, which can cause neuronal loss when activated in infectious, ischemic, traumatic, and neurodegenerative diseases. Caspase-8 has both prodeath and prosurvival roles, mediating apoptosis and/or preventing RIPK1-mediated necroptosis depending on cell type and stimulus. We found that inflammatory stimuli (LPS, lipoteichoic acid, or TNF-α) caused an increase in caspase-8 IETDase activity in primary rat microglia without inducing apoptosis. Inhibition of caspase-8 with either Z-VAD-fmk or IETD-fmk resulted in necrosis of activated microglia. Inhibition of caspases with Z-VAD-fmk did not kill non-activated microglia, or astrocytes and neurons in any condition. Necrostatin-1, a specific inhibitor of RIPK1, prevented microglial caspase inhibition-induced death, indicating death was by necroptosis. In mixed cerebellar cultures of primary neurons, astrocytes, and microglia, LPS induced neuronal loss that was prevented by inhibition of caspase-8 (resulting in microglial necroptosis), and neuronal death was restored by rescue of microglia with necrostatin-1. We conclude that the activation of caspase-8 in inflamed microglia prevents their death by necroptosis, and thus, caspase-8 inhibitors may protect neurons in the inflamed brain by selectively killing activated microglia.
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spelling pubmed-36109872013-03-29 Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia Fricker, Michael Vilalta, Anna Tolkovsky, Aviva M. Brown, Guy C. J Biol Chem Neurobiology Microglia are resident brain macrophages, which can cause neuronal loss when activated in infectious, ischemic, traumatic, and neurodegenerative diseases. Caspase-8 has both prodeath and prosurvival roles, mediating apoptosis and/or preventing RIPK1-mediated necroptosis depending on cell type and stimulus. We found that inflammatory stimuli (LPS, lipoteichoic acid, or TNF-α) caused an increase in caspase-8 IETDase activity in primary rat microglia without inducing apoptosis. Inhibition of caspase-8 with either Z-VAD-fmk or IETD-fmk resulted in necrosis of activated microglia. Inhibition of caspases with Z-VAD-fmk did not kill non-activated microglia, or astrocytes and neurons in any condition. Necrostatin-1, a specific inhibitor of RIPK1, prevented microglial caspase inhibition-induced death, indicating death was by necroptosis. In mixed cerebellar cultures of primary neurons, astrocytes, and microglia, LPS induced neuronal loss that was prevented by inhibition of caspase-8 (resulting in microglial necroptosis), and neuronal death was restored by rescue of microglia with necrostatin-1. We conclude that the activation of caspase-8 in inflamed microglia prevents their death by necroptosis, and thus, caspase-8 inhibitors may protect neurons in the inflamed brain by selectively killing activated microglia. American Society for Biochemistry and Molecular Biology 2013-03-29 2013-02-05 /pmc/articles/PMC3610987/ /pubmed/23386613 http://dx.doi.org/10.1074/jbc.M112.427880 Text en © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Neurobiology
Fricker, Michael
Vilalta, Anna
Tolkovsky, Aviva M.
Brown, Guy C.
Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title_full Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title_fullStr Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title_full_unstemmed Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title_short Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
title_sort caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia
topic Neurobiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610987/
https://www.ncbi.nlm.nih.gov/pubmed/23386613
http://dx.doi.org/10.1074/jbc.M112.427880
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