Neuromelanin activates proinflammatory microglia through a caspase-8-dependent mechanism

We have uncovered a caspase-dependent (caspase-8/caspase-3/7) signaling governing microglia activation and associated neurotoxicity. importantly,a profuse non-nuclear activation of cleaved caspases 8 and 3 was found in reactive microglia in the ventral mesencephalon from subjects with parkinson's disease,thus supporting the existence of endogenous factors activating microglia through a caspase-dependent mechanism. one obvious candidate is neuromelanin,which is an efficient proinflammogen in vivo and in vitro and has been shown to have a role in the pathogenesis of parkinson's disease. consequently,the goal of this study is to test whether synthetic neuromelanin activates microglia in a caspase-dependent manner. results: we found an in-vivo upregulation of cd16/32 (m1 marker) in iba1-immunolabeled microglia in the ventral mesencephalon after neuromelanin injection. in vitro experiments using bv2 cells,a microglia-derived cell line,demonstrated that synthetic neuromelanin induced a significant chemotactic response to bv2 microglial cells,along with typical morphological features of microglia activation,increased oxidative stress and induction of pattern-recognition receptors including toll-like receptor 2,nod2,and cd14. analysis of ietdase (caspase-8) and devdase (caspase-3/7) activities in bv2 cells demonstrated a modest but significant increase of both activities in response to neuromelanin treatment,in the absence of cell death. conclusions: caspase-8 inhibition prevented typical features of microglia activation,including morphological changes,a high rate of oxidative stress and expression of key proinflammatory cytokines and inos. © viceconte et al.; licensee biomed central.