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Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

  • Molecular Toxicology
  • Published:
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Abstract

Astrocytes, the largest cell population in the human brain, are powerful inflammatory effectors. Several studies have examined the interaction of activated astrocytes with neurons, but little is known yet about human neurotoxicity under such situations and about strategies of neuronal rescue. To address this question, immortalized murine astrocytes (IMA) were combined with human LUHMES neurons and stimulated with an inflammatory (TNF, IL-1) cytokine mix (CM). Neurotoxicity was studied both in co-cultures and in monocultures after transfer of conditioned medium from activated IMA. Interventions with >20 drugs were used to profile the model system. Control IMA supported neurons and protected them from neurotoxicants. Inflammatory activation reduced this protection, and prolonged exposure of co-cultures to CM triggered neurotoxicity. Neither the added cytokines nor the release of NO from astrocytes were involved in this neurodegeneration. The neurotoxicity-mediating effect of IMA was faithfully reproduced by human astrocytes. Moreover, glia-dependent toxicity was also observed, when IMA cultures were stimulated with CM, and the culture medium was transferred to neurons. Such neurotoxicity was prevented when astrocytes were treated by p38 kinase inhibitors or dexamethasone, whereas such compounds had no effect when added to neurons. Conversely, treatment of neurons with five different drugs, including resveratrol and CEP1347, prevented toxicity of astrocyte supernatants. Thus, the sequential IMA-LUHMES neuroinflammation model is suitable for separate profiling of both glial-directed and directly neuroprotective strategies. Moreover, direct evaluation in co-cultures of the same cells allows for testing of therapeutic effectiveness in more complex settings, in which astrocytes affect pharmacological properties of neurons.

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Abbreviations

PD:

Parkinson’s disease

DA:

Dopaminergic

MPP+ :

1-Methyl-4-phenyl-pyridinium

PARP:

Poly-(ADP-ribose)-polymerase

PLO:

Poly-l-ornithine

GDNF:

Glial-derived neurotrophic factor

IMA:

Immortalized mouse astrocytes

LDH:

Lactate dehydrogenase

DTNB:

5,5′-Dithiobis(2-nitrobenzoic acid)

GSH:

Glutathione

GSSG:

l-Glutathione oxidized

DHQ:

1,5-Isoquinolinediol

CEP1347:

(3,9-Bis[(ethylthio)methyl]-K-252a)

ROCK:

Rho kinase

DM:

Differentiation medium

DAT:

Dopamine transporter

LUHMES:

Lund human mesencephalic cells

TNF-α:

Tumor necrosis factor alpha

IL-1β:

Interleukin-1 beta

IFN-γ:

Interferon gamma

CM:

Cytokine mix

CCM:

Complete cytokine mix

L-NNA:

Nω-nitro-l-arginine

CNS:

Central nerve system

VMAT2:

Vesicular monoamine transporter

TH:

Tyrosine hydroxylase

NHA:

Normal human astrocytes

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

IkB:

NF-kappa-B inhibitor beta

COX2:

Cyclooxygenase-2

NOS:

Nitric oxide synthase

cAMP:

Cyclic adenosine monophosphate

NEP:

Neuroepithelial cells

mAGES:

Mouse astrocytes generated from embryonic stem cells

SNpc:

Substantia nigra pars compacta

LPS:

Lipopolysaccharides

NSE:

Neuron-specific enolase

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Acknowledgments

This work was supported by the Doerenkamp-Zbinden Foundation, the Land BW, the DFG (RTG1331; KoRS-CB), the BMBF, and University of Konstanz funds.

Author’s contribution

Liudmila Efremova and Petra Chovancova performed most experiments, analyzed data, and wrote the manuscript; Stefan Schildknecht, Martina Adam, and Simon Gutbier performed experiments and proofread the manuscript; Marcel Leist designed experiments and wrote the manuscript.

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    Authors and Affiliations

    1. Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, PO Box M657, 78457, Constance, Germany

      Liudmila Efremova, Petra Chovancova, Martina Adam, Simon Gutbier, Stefan Schildknecht & Marcel Leist

    2. Research Training Group 1331 (RTG1331), University of Konstanz, Constance, Germany

      Liudmila Efremova & Simon Gutbier

    3. Konstanz Research School Chemical Biology, University of Konstanz, Constance, Germany

      Petra Chovancova

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    1. Liudmila Efremova
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    Correspondence to Marcel Leist.

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    Liudmila Efremova and Petra Chovancova have contributed equally to this study.

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    Efremova, L., Chovancova, P., Adam, M. et al. Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation. Arch Toxicol 91, 231–246 (2017). https://doi.org/10.1007/s00204-016-1702-2

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