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

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 bloc...

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Autores principales: Gao, Liang, Brenner, David, Llorens-Bobadilla, Enric, Saiz-Castro, Gonzalo, Frank, Tobias, Wieghofer, Peter, Hill, Oliver, Thiemann, Meinolf, Karray, Saoussen, Prinz, Marco, Weishaupt, Jochen H., Martin-Villalba, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387281/
https://www.ncbi.nlm.nih.gov/pubmed/25779632
http://dx.doi.org/10.1084/jem.20132423
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author Gao, Liang
Brenner, David
Llorens-Bobadilla, Enric
Saiz-Castro, Gonzalo
Frank, Tobias
Wieghofer, Peter
Hill, Oliver
Thiemann, Meinolf
Karray, Saoussen
Prinz, Marco
Weishaupt, Jochen H.
Martin-Villalba, Ana
author_facet Gao, Liang
Brenner, David
Llorens-Bobadilla, Enric
Saiz-Castro, Gonzalo
Frank, Tobias
Wieghofer, Peter
Hill, Oliver
Thiemann, Meinolf
Karray, Saoussen
Prinz, Marco
Weishaupt, Jochen H.
Martin-Villalba, Ana
author_sort Gao, Liang
collection PubMed
description 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.
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spelling pubmed-43872812015-10-06 Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice Gao, Liang Brenner, David Llorens-Bobadilla, Enric Saiz-Castro, Gonzalo Frank, Tobias Wieghofer, Peter Hill, Oliver Thiemann, Meinolf Karray, Saoussen Prinz, Marco Weishaupt, Jochen H. Martin-Villalba, Ana J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2015-04-06 /pmc/articles/PMC4387281/ /pubmed/25779632 http://dx.doi.org/10.1084/jem.20132423 Text en © 2015 Gao et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Gao, Liang
Brenner, David
Llorens-Bobadilla, Enric
Saiz-Castro, Gonzalo
Frank, Tobias
Wieghofer, Peter
Hill, Oliver
Thiemann, Meinolf
Karray, Saoussen
Prinz, Marco
Weishaupt, Jochen H.
Martin-Villalba, Ana
Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title_full Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title_fullStr Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title_full_unstemmed Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title_short Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice
title_sort infiltration of circulating myeloid cells through cd95l contributes to neurodegeneration in mice
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387281/
https://www.ncbi.nlm.nih.gov/pubmed/25779632
http://dx.doi.org/10.1084/jem.20132423
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