The role of Galectin-3 in α-synuclein-induced microglial activation
Identifieur interne : 000214 ( Pmc/Curation ); précédent : 000213; suivant : 000215The role of Galectin-3 in α-synuclein-induced microglial activation
Auteurs : Antonio Boza-Serrano [Suède] ; Juan F. Reyes [Suède] ; Nolwen L. Rey [Suède, États-Unis] ; Hakon Leffler [Suède] ; Luc Bousset [France] ; Ulf Nilsson [Suède] ; Patrik Brundin [Suède, États-Unis] ; Jose Luis Venero [Espagne] ; Miguel Angel Burguillos [Suède] ; Tomas Deierborg [Suède]Source :
- Acta Neuropathologica Communications [ 2051-5960 ] ; 2014.
Abstract
Parkinson’s disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein.
We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1
We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.
The online version of this article (doi:10.1186/s40478-014-0156-0) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s40478-014-0156-0
PubMed: 25387690
PubMed Central: 4236422
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Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76 Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Deierborg, Tomas" sort="Deierborg, Tomas" uniqKey="Deierborg T" first="Tomas" last="Deierborg">Tomas Deierborg</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Experimental Neuroinflammation Laboratory, BMC, Lund University, 221 84 Lund, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Experimental Neuroinflammation Laboratory, BMC, Lund University, 221 84 Lund</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25387690</idno><idno type="pmc">4236422</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236422</idno><idno type="RBID">PMC:4236422</idno><idno type="doi">10.1186/s40478-014-0156-0</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000216</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein.</p></sec><sec><title>Results</title><p>We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1<italic>H</italic>-1,2,3-triazol-1-yl)-β-D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α-synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α-synuclein in the olfactory bulb of wild type mice and observed that some of the α-synuclein was taken up by activated microglia that were immunopositive for galectin-3.</p></sec><sec><title>Conclusions</title><p>We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s40478-014-0156-0) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Chaudhuri, Kr" uniqKey="Chaudhuri K">KR Chaudhuri</name></author><author><name sortKey="Schapira, Ah" uniqKey="Schapira A">AH Schapira</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spillantini, Mg" uniqKey="Spillantini M">MG Spillantini</name></author><author><name sortKey="Schmidt, Ml" uniqKey="Schmidt M">ML Schmidt</name></author><author><name sortKey="Lee, Vm" uniqKey="Lee V">VM Lee</name></author><author><name sortKey="Trojanowski, Jq" uniqKey="Trojanowski J">JQ 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Acta Neuropathol Commun</journal-id><journal-id journal-id-type="iso-abbrev">Acta Neuropathol Commun</journal-id><journal-title-group><journal-title>Acta Neuropathologica Communications</journal-title></journal-title-group><issn pub-type="epub">2051-5960</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25387690</article-id><article-id pub-id-type="pmc">4236422</article-id><article-id pub-id-type="publisher-id">156</article-id><article-id pub-id-type="doi">10.1186/s40478-014-0156-0</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>The role of Galectin-3 in α-synuclein-induced microglial activation</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Boza-Serrano</surname><given-names>Antonio</given-names></name><address><email>antonio.boza_serrano@med.lu.se</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Reyes</surname><given-names>Juan F</given-names></name><address><email>juan.reyespalacios@epfl.ch</email></address><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Rey</surname><given-names>Nolwen L</given-names></name><address><email>nolwen.rey@vai.org</email></address><xref ref-type="aff" rid="Aff2"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Leffler</surname><given-names>Hakon</given-names></name><address><email>Hakon.Leffler@med.lu.se</email></address><xref ref-type="aff" rid="Aff6"></xref></contrib><contrib contrib-type="author"><name><surname>Bousset</surname><given-names>Luc</given-names></name><address><email>bousset@lebs.cnrs-gif.fr</email></address><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Nilsson</surname><given-names>Ulf</given-names></name><address><email>ulf.nilsson@chem.lu.se</email></address><xref ref-type="aff" rid="Aff7"></xref></contrib><contrib contrib-type="author"><name><surname>Brundin</surname><given-names>Patrik</given-names></name><address><email>patrik.brundin@vai.org</email></address><xref ref-type="aff" rid="Aff2"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Venero</surname><given-names>Jose Luis</given-names></name><address><email>jlvenero@us.es</email></address><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Burguillos</surname><given-names>Miguel Angel</given-names></name><address><email>miguel.burguillos@ki.se</email></address><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Deierborg</surname><given-names>Tomas</given-names></name><address><email>tomas.deierborg@med.lu.se</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><label></label>Experimental Neuroinflammation Laboratory, BMC, Lund University, 221 84 Lund, Sweden</aff><aff id="Aff2"><label></label>Neuronal Survival Unit, BMC, Lund University, 221 84 Lund, Sweden</aff><aff id="Aff3"><label></label>Translational Parkinson’s Disease Research, Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI USA</aff><aff id="Aff4"><label></label>Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden</aff><aff id="Aff5"><label></label>Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Facultad de Farmacia, Sevilla, Spain</aff><aff id="Aff6"><label></label>Section MIG, Department of Laboratory Medicine, Solvegatan 23, Lund University, 223 62 Lund, Sweden</aff><aff id="Aff7"><label></label>Centre for Analysis and Synthesis, Department of Chemistry, Lund University, PO Box 124, 221 00 Lund, Sweden</aff><aff id="Aff8"><label></label>Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Bat 34, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</aff></contrib-group><pub-date pub-type="epub"><day>12</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="collection"><year>2014</year></pub-date><volume>2</volume><elocation-id>156</elocation-id><history><date date-type="received"><day>1</day><month>9</month><year>2014</year></date><date date-type="accepted"><day>17</day><month>10</month><year>2014</year></date></history><permissions><copyright-statement>© Boza-Serrano et al.; licensee BioMed Central Ltd. 2014</copyright-statement><license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>Parkinson’s disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein.</p></sec><sec><title>Results</title><p>We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1<italic>H</italic>-1,2,3-triazol-1-yl)-β-D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α-synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α-synuclein in the olfactory bulb of wild type mice and observed that some of the α-synuclein was taken up by activated microglia that were immunopositive for galectin-3.</p></sec><sec><title>Conclusions</title><p>We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s40478-014-0156-0) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Microglia</kwd><kwd>Galectin-3</kwd><kwd>Neuroinflammation</kwd><kwd>α-synuclein</kwd><kwd>Parkinson’s disease</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2014</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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