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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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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. |
format | Online Article Text |
id | pubmed-4387281 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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