title: Tollip, an early regulator of the acute inflammatory response in the substantia nigra.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Department of Clinical Neuroscience, Lausanne University Hospital, Lausanne, Switzerland. marie.humbert-claude@chuv.ch.
authors.forename: Marie
authors.identifier: 0000-0001-6610-1662
authors.initials: M
authors.lastname: Humbert-Claude
authors.affiliation: Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Department of Clinical Neuroscience, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Duc
authors.affiliation: Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Prilly, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Dwir
authors.affiliation: Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Department of Clinical Neuroscience, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Thieren
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Sandström von Tobel
authors.affiliation: Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Begka
authors.affiliation: FIRALIS SA, Huningue, France.
authors.forename: F
authors.initials: F
authors.lastname: Legueux
authors.affiliation: Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Velin
authors.affiliation: Service of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: M H
authors.initials: MH
authors.lastname: Maillard
authors.affiliation: Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Prilly, Lausanne, Switzerland.
authors.forename: K Q
authors.initials: KQ
authors.lastname: Do
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Monnet-Tschudi
authors.affiliation: Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Department of Clinical Neuroscience, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Tenenbaum
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C485837:Tollip protein, mouse; D049452:Green Fluorescent Proteins
keywords: Adeno-associated viral vector; Cytokine; Lipopolysaccharide; Neuroinflammation; Oxidative stress; Parkinson’s disease; Substantia nigra; Toll-like interacting protein; Tollip; iNOS