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Journal of Neuroinflammation

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Open Access 01-12-2015 | Research

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

Authors: Nikenza Viceconte, Miguel A Burguillos, Antonio J Herrera, Rocío M De Pablos, Bertrand Joseph, José L Venero

Published in: Journal of Neuroinflammation | Issue 1/2015

Abstract

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.

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Title: Neuromelanin activates proinflammatory microglia through a caspase-8-dependent mechanism
Authors: Nikenza Viceconte
Miguel A Burguillos
Antonio J Herrera
Rocío M De Pablos
Bertrand Joseph
José L Venero
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-014-0228-x

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

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