Caspase signalling controls microglia activation and neurotoxicity
Open accessAbstract
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
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- Authors
- Burguillos, M. A., Deierborg, T., Kavanagh, E., Persson, A., Hajji, N., Garcia-Quintanilla, A., Cano, J., Brundin, P., Englund, E., Venero, J. L., & Joseph, B.
- Affiliations
- Lund University (SE)
- Karolinska Institutet (SE)
- Skåne University Hospital (SE)
- Instituto de Biomedicina de Sevilla (ES)
- Corresponding author
- Venero, Jose L.
- Joseph, Bertrand
- Venue
- Nature
- Published
- 2011-03-09
- Volume
- 472
- Issue
- 7343
- Pages
- 319-324
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2141677575
- Cited by
- 585
- References
- 48
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 42 · 2023: 30 · 2022: 42 · 2021: 40 · 2020: 37 · 2019: 34 · 2018: 35 · 2017: 44 · 2016: 35 · 2015: 44 · 2014: 53 · 2013: 52 · 2012: 42
- FWCI
- 29.48
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- microglial activation, caspase-8, caspase 3/7, neuroinflammation, neurotoxicity, protein kinase C delta, caspase inhibition, neuroprotection, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Dopamine, Enzyme Activation, Frontal Lobe, Humans, Lipopolysaccharides, Parkinson Disease, Substantia Nigra, Signal Transduction, Cell Death, Neostriatum, Microglia, Caspases, Neurotoxicity Syndromes, Toll-Like Receptor 4, Mice, Rats, Protein Kinase C-delta, Caspase 3, Caspase 7, Caspase 8, Gene Knockdown Techniques, Caspase Inhibitors
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