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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Tollip, an early regulator of the acute inflammatory response in the substantia nigra

Authors: Marie Humbert-Claude, D. Duc, D. Dwir, L. Thieren, J. Sandström von Tobel, C. Begka, F. Legueux, D. Velin, M. H. Maillard, K. Q. Do, F. Monnet-Tschudi, L. Tenenbaum

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson’s disease.

Methods

We first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice.

Results

We report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2′-deoxyguanosine and nitrotyrosine immunostaining, respectively.

Conclusions

Altogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson’s disease, Tollip may be a potential target for neuroprotection.
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Metadata
Title
Tollip, an early regulator of the acute inflammatory response in the substantia nigra
Authors
Marie Humbert-Claude
D. Duc
D. Dwir
L. Thieren
J. Sandström von Tobel
C. Begka
F. Legueux
D. Velin
M. H. Maillard
K. Q. Do
F. Monnet-Tschudi
L. Tenenbaum
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0766-5

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