title: 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.
authors: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, United Kingdom. michael.fricker@gmail.com
authors: Michael
authors: M
authors: Fricker
authors: Anna
authors: A
authors: Vilalta
authors: Aviva M
authors: AM
authors: Tolkovsky
authors: Guy C
authors: GC
authors: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000737:chemistry*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D009336:Necrosis; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C507699:necrostatin-1; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8
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