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Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia.

Abstract
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.
AuthorsMichael Fricker, Anna Vilalta, Aviva M Tolkovsky, Guy C Brown
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 13 Pg. 9145-52 (Mar 29 2013) ISSN: 1083-351X [Electronic] United States
PMID23386613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Caspase Inhibitors
  • Imidazoles
  • Indoles
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • necrostatin-1
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8
Topics
  • Animals
  • Apoptosis
  • Caspase 8 (chemistry)
  • Caspase Inhibitors (pharmacology)
  • Cell Survival
  • Cells, Cultured
  • Imidazoles (metabolism)
  • Indoles (metabolism)
  • Inflammation
  • Lipopolysaccharides (metabolism)
  • Microglia (metabolism)
  • Models, Biological
  • Necrosis
  • Neuroglia (metabolism)
  • Neurons (metabolism)
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
  • Signal Transduction
  • Tumor Necrosis Factor-alpha (metabolism)

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