TY - JOUR
T1 - Tollip, an early regulator of the acute inflammatory response in the substantia nigra
AU - Humbert-Claude, Marie
AU - Duc, D.
AU - Dwir, D.
AU - Thieren, L.
AU - Sandström von Tobel, J.
AU - Begka, C.
AU - Legueux, F.
AU - Velin, D.
AU - Maillard, M. H.
AU - Do, K. Q.
AU - Monnet-Tschudi, F.
AU - Tenenbaum, L.
N1 - Funding Information:
This work was supported by the Swiss National Research Foundation (grant number 31003A-127177 to LT and grant number 310030_141145 to DV), by the EU FP7 Marie Curie Industry-Academy Partnerships and Pathways grant (contract n° 286071 to LT), by the Swiss Center for Applied Human Toxicology (SCAHT) to FTM, and by Novartis, San Salvatore, and Emma Muschamp Foundations to MM.
Publisher Copyright:
© 2016 The Author(s).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/12/7
Y1 - 2016/12/7
N2 - 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.
AB - 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.
KW - Adeno-associated viral vector
KW - Cytokine
KW - INOS
KW - Lipopolysaccharide
KW - Neuroinflammation
KW - Oxidative stress
KW - Parkinson's disease
KW - Substantia nigra
KW - Toll-like interacting protein
KW - Tollip
UR - http://www.scopus.com/inward/record.url?scp=85002915745&partnerID=8YFLogxK
U2 - 10.1186/s12974-016-0766-5
DO - 10.1186/s12974-016-0766-5
M3 - Article
C2 - 27927222
AN - SCOPUS:85002915745
SN - 1742-2094
VL - 13
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 303
ER -