[Show abstract][Hide abstract] ABSTRACT: Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, differentiation and the interrelation of these with cell proliferation.
Cell death and differentiation 11/2012; 20(2). DOI:10.1038/cdd.2012.151 · 8.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microglia are resident brain macrophages, which can cause neuronal loss when activated in infectious, ischaemic, traumatic and neurodegenerative diseases. Caspase-8 has both pro-death and pro-survival roles, mediating apoptosis and/or preventing RIPK1-mediated necroptosis depending on cell type and stimulus. We found that inflammatory stimuli (LPS, LTA or TNF-α) caused an increase in caspase-8 IETDase activity in primary rat microglia without inducing apoptosis. Inhibition of caspase-8 activity with either zVAD-fmk or IETD-fmk resulted in necrosis of activated microglia. Inhibition of caspases with zVAD-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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