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Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia.
Fricker, Michael; Vilalta, Anna; Tolkovsky, Aviva M; Brown, Guy C.
Afiliación
  • Fricker M; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, United Kingdom. michael.fricker@gmail.com
J Biol Chem ; 288(13): 9145-52, 2013 Mar 29.
Article en En | MEDLINE | ID: mdl-23386613
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Apoptosis / Microglía / Caspasa 8 / Inhibidores de Caspasas / Necrosis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Biol Chem Año: 2013 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Apoptosis / Microglía / Caspasa 8 / Inhibidores de Caspasas / Necrosis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Biol Chem Año: 2013 Tipo del documento: Article País de afiliación: Reino Unido