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J Exp Med. 2015 Apr 6;212(4):469-80. doi: 10.1084/jem.20132423. Epub 2015 Mar 16.

Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice.

Author information

1
Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Department of Neurology, University Medical Center, Georg-August-University, 37075 Göttingen, Germany.
3
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.
4
Apogenix GmbH, 69120 Heidelberg, Germany.
5
Institut National de la Santé et de la Recherche Médicale (INSERM), U1160, Université Paris Diderot, 75010 Paris, France.
6
Department of Neurology, University of Ulm, 89081 Ulm, Germany.
7
Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany a.martin-villalba@dkfz.de.

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.

PMID:
25779632
PMCID:
PMC4387281
DOI:
10.1084/jem.20132423
[Indexed for MEDLINE]
Free PMC Article

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