Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease
Identifieur interne : 002324 ( Main/Corpus ); précédent : 002323; suivant : 002325Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease
Auteurs : Ana I. Rojo ; Nadia G. Innamorato ; Ana M. Martín-Moreno ; María L. De Ceballos ; Masayuki Yamamoto ; Antonio CuadradoSource :
- Glia [ 0894-1491 ] ; 2010-04.
English descriptors
Abstract
Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.
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DOI: 10.1002/glia.20947
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The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ana I. Rojo</name><affiliations><json:string>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</json:string><json:string>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</json:string></affiliations></json:item><json:item><name>Nadia G. Innamorato</name><affiliations><json:string>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</json:string><json:string>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</json:string></affiliations></json:item><json:item><name>Ana M. Martín‐Moreno</name><affiliations><json:string>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</json:string><json:string>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</json:string></affiliations></json:item><json:item><name>María L. De Ceballos</name><affiliations><json:string>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</json:string><json:string>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</json:string></affiliations></json:item><json:item><name>Masayuki Yamamoto</name><affiliations><json:string>Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan</json:string></affiliations></json:item><json:item><name>Antonio Cuadrado</name><affiliations><json:string>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</json:string><json:string>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>innate immune system</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurodegenerative diseases</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>heme oxygenase‐1</value></json:item></subject><articleId><json:string>GLIA20947</json:string></articleId><language><json:string>eng</json:string></language><abstract>Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. 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Rojo and Nadia G. Innamorato should be considered as first authors.</note><affiliation>Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</affiliation><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation></author><author><persName><forename type="first">Nadia G.</forename><surname>Innamorato</surname></persName><note type="biography">Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</note><affiliation>Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</affiliation><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation></author><author><persName><forename type="first">Ana M.</forename><surname>Martín‐Moreno</surname></persName><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</affiliation></author><author><persName><forename type="first">María L.</forename><surname>De Ceballos</surname></persName><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</affiliation></author><author><persName><forename type="first">Masayuki</forename><surname>Yamamoto</surname></persName><affiliation>Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan</affiliation></author><author><persName><forename type="first">Antonio</forename><surname>Cuadrado</surname></persName><note type="correspondence"><p>Correspondence: Instituto de Investigaciones Biomédicas “A. Sols” UAM‐CSIC. Arturo Duperier 4, 28029 Madrid, Spain</p></note><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation></author></analytic><monogr><title level="j">Glia</title><title level="j" type="abbrev">Glia</title><idno type="pISSN">0894-1491</idno><idno type="eISSN">1098-1136</idno><idno type="DOI">10.1002/(ISSN)1098-1136</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-04"></date><biblScope unit="volume">58</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="588">588</biblScope><biblScope unit="page" to="598">598</biblScope></imprint></monogr><idno type="istex">C2FD69B7B8C27492BD436920C88B658D0F43E23F</idno><idno type="DOI">10.1002/glia.20947</idno><idno type="ArticleID">GLIA20947</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>innate immune system</term></item><item><term>neurodegenerative diseases</term></item><item><term>heme oxygenase‐1</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Original Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-07-29">Received</change><change when="2009-10-15">Registration</change><change when="2010-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C2FD69B7B8C27492BD436920C88B658D0F43E23F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1098-1136</doi><issn type="print">0894-1491</issn><issn type="electronic">1098-1136</issn><idGroup><id type="product" value="GLIA"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="GLIA">Glia</title><title type="short">Glia</title></titleGroup></publicationMeta><publicationMeta level="part" position="50"><doi origin="wiley" registered="yes">10.1002/glia.v58:5</doi><numberingGroup><numbering type="journalVolume" number="58">58</numbering><numbering type="journalIssue">5</numbering></numberingGroup><coverDate startDate="2010-04">April 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="70" status="forIssue"><doi origin="wiley" registered="yes">10.1002/glia.20947</doi><idGroup><id type="unit" value="GLIA20947"></id></idGroup><countGroup><count type="pageTotal" number="11"></count></countGroup><titleGroup><title type="articleCategory">Original Article</title><title type="tocHeading1">Original Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2009 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2009-07-29"></event><event type="manuscriptAccepted" date="2009-10-15"></event><event type="publishedOnlineEarlyUnpaginated" date="2009-11-11"></event><event type="firstOnline" date="2009-11-11"></event><event type="publishedOnlineFinalForm" date="2010-02-05"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.6 mode:FullText source:FullText result:FullText" date="2010-04-21"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-26"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-24"></event></eventGroup><numberingGroup><numbering type="pageFirst">588</numbering><numbering type="pageLast">598</numbering></numberingGroup><correspondenceTo>Instituto de Investigaciones Biomédicas “A. 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Arturo Duperier 4, 28029 Madrid, Spain</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:GLIA.GLIA20947.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="8"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="47"></count><count type="wordTotal" number="7400"></count></countGroup><titleGroup><title type="main" xml:lang="en">Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease</title><title type="short" xml:lang="en">N<sc>RF</sc>2 Regulates Microglial Dynamics</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" noteRef="#fn1"><personName><givenNames>Ana I.</givenNames><familyName>Rojo</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2" noteRef="#fn1"><personName><givenNames>Nadia G.</givenNames><familyName>Innamorato</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af3"><personName><givenNames>Ana M.</givenNames><familyName>Martín‐Moreno</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af3"><personName><givenNames>María L.</givenNames><familyName>De Ceballos</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Masayuki</givenNames><familyName>Yamamoto</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Antonio</givenNames><familyName>Cuadrado</familyName></personName><contactDetails><email>antonio.cuadrado@uam.es</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="ES" type="organization"><unparsedAffiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="ES" type="organization"><unparsedAffiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="ES" type="organization"><unparsedAffiliation>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="JP" type="organization"><unparsedAffiliation>Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">innate immune system</keyword><keyword xml:id="kwd2">neurodegenerative diseases</keyword><keyword xml:id="kwd3">heme oxygenase‐1</keyword></keywordGroup><fundingInfo><fundingAgency>Spanish Ministry of Science and Innovation</fundingAgency><fundingNumber>SAF2007‐62646</fundingNumber></fundingInfo><fundingInfo><fundingAgency>FPU fellowship of Universidad Autónoma of Madrid</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08941491:media:glia20947:GLIA_20947_sm_suppinfoFigure1"></mediaResource><caption>Supporting Information Figure 1. Conversion of MPTP to MPP+ in Nrf2−/− and Nrf2+/+ mice. A, Time‐dependent accumulation of MPP+ in STR of Nrf2−/− and Nrf2+/+ mice that received one single intraperitoneal injection of 20 mg/kg MPTP. B, immunoblot of STR protein extracts. Upper panel, anti‐monoamine oxidase‐B (MAO‐B) antibody. Middle panel, anti‐dopamine transporter (DAT) antibody. Lower panel, anti‐β‐actin antibody sowing similar protein load. C and D, densitometric quantification of MAO‐B and DAT protein levels after normalization by β‐actin. Results are representative of 4 animals per group. Bars indicate mean ± SD. According to a Student's t test, the differences between the indicated groups are not statically significant (P > 0.05).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08941491:media:glia20947:GLIA_20947_sm_suppinfoTable1"></mediaResource><caption>Table 1. Genes and primers for quantitative PCR amplification.</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP<sup>+</sup>‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>NRF2 Regulates Microglial Dynamics</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Ana I.</namePart><namePart type="family">Rojo</namePart><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation><description>Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nadia G.</namePart><namePart type="family">Innamorato</namePart><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation><description>Ana I. Rojo and Nadia G. Innamorato should be considered as first authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ana M.</namePart><namePart type="family">Martín‐Moreno</namePart><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">María L.</namePart><namePart type="family">De Ceballos</namePart><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Neurobiología Celular, Molecular y Desarrollo, Instituto Cajal, CSIC, Madrid, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Masayuki</namePart><namePart type="family">Yamamoto</namePart><affiliation>Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Antonio</namePart><namePart type="family">Cuadrado</namePart><affiliation>Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain</affiliation><affiliation>Dpto. de Bioquímica and Instituto de Investigaciones Biomédicas “Alberto Sols” UAM‐CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain</affiliation><description>Correspondence: Instituto de Investigaciones Biomédicas “A. Sols” UAM‐CSIC. Arturo Duperier 4, 28029 Madrid, Spain</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2010-04</dateIssued><dateCaptured encoding="w3cdtf">2009-07-29</dateCaptured><dateValid encoding="w3cdtf">2009-10-15</dateValid><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">8</extent><extent unit="references">47</extent><extent unit="words">7400</extent></physicalDescription><abstract lang="en">Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.</abstract><note type="funding">Spanish Ministry of Science and Innovation - No. SAF2007‐62646; </note><note type="funding">FPU fellowship of Universidad Autónoma of Madrid</note><subject lang="en"><genre>Keywords</genre><topic>innate immune system</topic><topic>neurodegenerative diseases</topic><topic>heme oxygenase‐1</topic></subject><relatedItem type="host"><titleInfo><title>Glia</title></titleInfo><titleInfo type="abbreviated"><title>Glia</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Supporting Information Figure 1. Conversion of MPTP to MPP+ in Nrf2−/− and Nrf2+/+ mice. A, Time‐dependent accumulation of MPP+ in STR of Nrf2−/− and Nrf2+/+ mice that received one single intraperitoneal injection of 20 mg/kg MPTP. B, immunoblot of STR protein extracts. Upper panel, anti‐monoamine oxidase‐B (MAO‐B) antibody. Middle panel, anti‐dopamine transporter (DAT) antibody. Lower panel, anti‐β‐actin antibody sowing similar protein load. C and D, densitometric quantification of MAO‐B and DAT protein levels after normalization by β‐actin. Results are representative of 4 animals per group. Bars indicate mean ± SD. According to a Student's t test, the differences between the indicated groups are not statically significant (P > 0.05). - Table 1. Genes and primers for quantitative PCR amplification. - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0894-1491</identifier><identifier type="eISSN">1098-1136</identifier><identifier type="DOI">10.1002/(ISSN)1098-1136</identifier><identifier type="PublisherID">GLIA</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>58</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>588</start><end>598</end><total>11</total></extent></part></relatedItem><identifier type="istex">C2FD69B7B8C27492BD436920C88B658D0F43E23F</identifier><identifier type="DOI">10.1002/glia.20947</identifier><identifier type="ArticleID">GLIA20947</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2009 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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