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Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration

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Abstract

Purpose

Activation of the innate immune system plays a significant role in pathologies of the central nervous system (CNS). In order to follow disease progression and evaluate effectiveness of potential treatments involved in neuroinflammation, it is important to track neuroinflammatory markers in vivo longitudinally. The translocator protein (TSPO) is used as a target to image neuroinflammation as its expression is upregulated in reactive glial cells during CNS pathologies. However, it remains unclear in which microglial phenotypes TSPO levels are upregulated, as microglia can display a plethora of activation states that can be protective or detrimental to the CNS.

Procedures

We assessed the levels of TSPO transcripts in cultured microglia that were polarized into pro- and anti-inflammatory states in vitro and in the brain of mice in which an anti-inflammatory environment was induced in vivo. In addition, we used a mouse model of peroxisomal multifunctional protein-2 (MFP2) deficiency that exhibits widespread neuroinflammation despite no neuronal loss and monitored TSPO expression by immunohistochemistry and by imaging using the TSPO radiotracer [18F]DPA-714.

Results

TSPO expression was selectively increased in so-called classically activated or M1 microglia but not in alternatively activated or M2 microglia in vitro. In agreement, TSPO transcript levels were not induced in an anti-inflammatory brain environment. We found that both transcript and protein levels of TSPO are significantly increased in the brain of Mfp2 −/− compared to those of the control mice and TSPO immunoreactivity colocalized predominantly with microglia in Mfp2 −/− brain. In vitro and ex vivo autoradiography in Mfp2 −/− mice using the TSPO radiotracer [18F]DPA-714 confirmed increased expression of TSPO. These data demonstrate that TSPO imaging reveals microgliosis in non-neurodegenerative brain pathologies.

Conclusions

We show that induced TSPO expression marks a pro-inflammatory brain environment that is not necessarily accompanied by neuronal loss.

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Acknowledgments

The authors wish to thank Benno Das, Lies Pauwels, Julie Cornelis, and Ann Bouché for their excellent technical assistance. This work was funded by grants from the Fonds Wetenschappelijk Onderzoek Vlaanderen (G.0675.12 and G.0A15.13), KU Leuven (OT12/78), European Union’s Seventh Framework Programme [FP7/2007-2013], INMiND (grant agreement no. 278850), ERA-NET Neuron (Micromet) and Programme financing KU Leuven IMIR.

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Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Cell Metabolism, KU Leuven - University of Leuven, Campus Gasthuisberg O/N2, Herestraat 49, 3000, Leuven, Belgium

    Lien Beckers, Ivana Geric & Myriam Baes

  2. Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Radiopharmacy, KU Leuven - University of Leuven, Leuven, Belgium

    Dieter Ory, Lieven Declercq & Guy Bormans

  3. Department of Nuclear Medicine and Molecular Imaging, KU Leuven- University of Leuven, Leuven, Belgium

    Michel Koole

  4. School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia

    Michael Kassiou

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  1. Lien Beckers
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Corresponding author

Correspondence to Myriam Baes.

Ethics declarations

All animal experiments were performed in accordance with the “Guidelines for Care and Use of Experimental Animals” and fully approved by the Research Ethical committee of the KU Leuven (#190/2012).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Lien Beckers and Dieter Ory are equal first authors

Guy Bormans and Myriam Baes are equal last authors

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Beckers, L., Ory, D., Geric, I. et al. Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration. Mol Imaging Biol 20, 94–102 (2018). https://doi.org/10.1007/s11307-017-1099-1

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