title: Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice.
abstract: Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system-resident microglia and infiltrating immune cells contribute to the degeneration of dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease.
authors.affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Liang
authors.initials: L
authors.lastname: Gao
authors.affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Enric
authors.initials: E
authors.lastname: Llorens-Bobadilla
authors.affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Saiz-Castro
authors.affiliation: Department of Neurology, University Medical Center, Georg-August-University, 37075 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Frank
authors.affiliation: Institute of Neuropathology, Faculty of Biology, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79098 Freiburg, Germany Institute of Neuropathology, Faculty of Biology, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79098 Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wieghofer
authors.affiliation: Apogenix GmbH, 69120 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hill
authors.affiliation: Apogenix GmbH, 69120 Heidelberg, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Thiemann
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1160, Université Paris Diderot, 75010 Paris, France.
authors.forename: Saoussen
authors.initials: S
authors.lastname: Karray
authors.affiliation: Institute of Neuropathology, Faculty of Biology, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79098 Freiburg, Germany Institute of Neuropathology, Faculty of Biology, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79098 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Neurology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany a.martin-villalba@dkfz.de.
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003342:Corpus Striatum / Q000276:immunology / Q000473:pathology; D004298:Dopamine / Q000235:genetics / Q000276:immunology; D059290:Dopaminergic Neurons / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000276:immunology
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor; D004298:Dopamine