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Caspase signalling controls microglia activation and neurotoxicity

Nature volume 472, pages 319–324 (2011)Cite this article

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Abstract

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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Figure 1: LPS-induced DEVDase activity regulates microglia activation but not cell death.
Figure 2: Knockdown of caspase-3 or caspase-7 decreases microglia activation in response to LPS.
Figure 3: Caspase-8 activity controls LPS-induced caspase-3/7 activation.
Figure 4: Caspase-3/7 regulates microglia activation through the PKC-δ pathway.
Figure 5: In vivo inhibition of the caspase-dependent pathways prevents microglia activation.
Figure 6: Activation of caspase-3 and caspase-8 in microglia in brain from individuals with PD and AD.

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Acknowledgements

We thank A. Gorman, O. Hermanson, M. Malewicz, S. Orrenius, T. Panaretakis and B. Zhivotovsky for discussion, and L. Hjortsberg, M. Reyland and S. Ceccatelli for providing us with reagents. M. Carballo, JL. Ribas, A. Fernández and B. Haraldsson provided qualified technical support. This work has been supported by grants from the Spanish Ministerio de Ciencia y Tecnología (SAF2006-04119 and 2009-13778), the Swedish Research Council, the Parkinson Foundation of Sweden, the Swedish Alzheimer Foundation and the Swedish Cancer Society. M.A.B., T.D. and P.B. are members of Neurofortis and Bagadilico, both of which are research environments sponsored by the Swedish Research Council.

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  1. Nabil Hajji

    Present address: Present address: Department of Experimental Medicine and Toxicology, Division of Investigative Science, Imperial College London, UK.,

Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, 171 76, Sweden

    Miguel A. Burguillos, Edel Kavanagh, Nabil Hajji & Bertrand Joseph

  2. Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla, Sevilla, 41012, Spain

    Miguel A. Burguillos, Josefina Cano & Jose L. Venero

  3. Department of Experimental Medical Science, Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund, 221 84, Sweden

    Miguel A. Burguillos, Tomas Deierborg & Patrik Brundin

  4. Department of Pathology, Division of Neuropathology, Lund University Hospital, Lund, 221 85, Sweden

    Annette Persson & Elisabet Englund

  5. Servicio de Biología, Centro de Investigación, Tecnología e Innovación, Universidad de Sevilla (CITIUS), Sevilla, 41012, Spain

    Albert Garcia-Quintanilla

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Contributions

M.A.B. performed all the experiments except as otherwise noted. qPCR was performed by A.G.-Q. and E.K. J.L.V. and J.C. collaborated in doing surgery and further dissecting the animal brains. M.A.B. and T.D. performed primary cell culture experiments and cytokine analysis. E.K. collaborated in performing the caspase activity assay. B.J. and E.K. collaborated in performing FACS. B.J. collaborated also in the confocal imaging analysis. E.E. did the neuropathology of the individuals with PD and AD and the controls. A.P. prepared tissue and participated in the morphological assessment of human brain specimens. N.H. and P.B. were involved in study design. M.A.B., J.L.V. and B.J. designed the study, analysed and interpreted the data. All authors discussed the results and commented on or edited the manuscript. The first draft of the paper was written by B.J. J.L.V. and B.J. share senior authorship of the paper. T.D and E.K. share second authorship.

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Correspondence to Jose L. Venero or Bertrand Joseph.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-20 with legends, Supplementary Tables 1-3 and legends for Supplementary Movies 1-2. (PDF 20300 kb)

Supplementary Movie 1

This movie shows 3D confocal analysis of cleaved caspase-3 (in green) in lipopolysaccharide treated BV2 microglia cells. Nuclear and plasma membrane compartments were labeled with DAPI (Blue) and red fluorescent cholera toxin subunit B conjugates respectively. LPS-induced caspase-3 activation in BV2 microglia cells is restricted to plasma membrane compartment. (MOV 1592 kb)

Supplementary Movie 2

This movie shows 3D confocal analysis of cleaved caspase-3 (in green) in staurospaurine treated BV2 microglia cells. Nuclear and plasma membrane compartments were labeled with DAPI (Blue) and red fluorescent cholera toxin subunit B conjugates respectively. STS-induced caspase-3 activation in BV2 microglia cells accumulates in the nuclear compartment. (MOV 1349 kb)

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Burguillos, M., Deierborg, T., Kavanagh, E. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011). https://doi.org/10.1038/nature09788

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