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.