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

Journal of Neuroinflammation

José L Venero²  Bertrand Joseph³  Rocío M De Pablos²  Antonio J Herrera²  Miguel A Burguillos¹  Nikenza Viceconte⁴ 

[1] Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, E1 2AT, United Kingdom;Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, 41013, Spain;Department of Oncology-Pathology, Karolinska Institutet, Cancer Centrum Karolinska, Stockholm, 17176, Sweden;Present address: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, 17177, Sweden

关键词: Parkinson’s disease;    neuroinflammation;    microglia;    cytokines;    caspase-8;    caspase-3;   

Others  :  1133401
DOI  :  10.1186/s12974-014-0228-x

 received in 2014-09-09, accepted in 2014-12-21,  发布年份 2015

【 摘 要 】

Background

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.

【 授权许可】

   
2015 Viceconte et al.; licensee BioMed Central.

【 图 表 】

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