Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease
Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the rol...
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| description | Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer's disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation.
To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn.
We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn.
Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD. |
| doi_str_mv | 10.1371/journal.pone.0140566 |
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To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn.
We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn.
Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0140566</identifier><identifier>PMID: 26469270</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; alpha-Synuclein - pharmacology ; Alzheimer's disease ; Animal models ; Animals ; Antigens ; Beads ; Brain ; Chemokine CX3CL1 - metabolism ; CX3C Chemokine Receptor 1 ; CX3CR1 protein ; Cytokines ; Dependovirus - genetics ; Disease Models, Animal ; Dopamine ; Dopamine receptors ; Dopaminergic Neurons - metabolism ; Fluorescence ; Fractalkine ; Gene Knockout Techniques ; Genetic Vectors ; Genomes ; Humans ; Immunoglobulin G ; Inflammation ; Inflammatory response ; Internalization ; Ligands ; Mice ; Microglia ; Microglia - drug effects ; Movement disorders ; Multiple sclerosis ; Neurodegeneration ; Neurodegenerative diseases ; Neurology ; Neurons ; Neurotoxicity ; Neurotoxins ; Parkinson Disease - genetics ; Parkinson Disease - immunology ; Parkinson's disease ; Pathogenesis ; Phagocytosis ; Proteins ; Receptors, Chemokine - genetics ; Receptors, Chemokine - metabolism ; Rodents ; Signal transduction ; Signaling ; Substantia nigra ; Synuclein ; Therapeutic applications ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2015-10, Vol.10 (10), p.e0140566</ispartof><rights>2015 Thome et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Thome et al 2015 Thome et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-c1b3f702a4dcc6f3430c18a491d343184bf3effb3e4d2c444a526e1038ac6e6d3</citedby><cites>FETCH-LOGICAL-c526t-c1b3f702a4dcc6f3430c18a491d343184bf3effb3e4d2c444a526e1038ac6e6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607155/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607155/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26469270$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tansey, Malú G.</contributor><creatorcontrib>Thome, Aaron D</creatorcontrib><creatorcontrib>Standaert, David G</creatorcontrib><creatorcontrib>Harms, Ashley S</creatorcontrib><title>Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer's disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation.
To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn.
We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn.
Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD.</description><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - metabolism</subject><subject>alpha-Synuclein - pharmacology</subject><subject>Alzheimer's disease</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antigens</subject><subject>Beads</subject><subject>Brain</subject><subject>Chemokine CX3CL1 - metabolism</subject><subject>CX3C Chemokine Receptor 1</subject><subject>CX3CR1 protein</subject><subject>Cytokines</subject><subject>Dependovirus - genetics</subject><subject>Disease Models, Animal</subject><subject>Dopamine</subject><subject>Dopamine receptors</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Fluorescence</subject><subject>Fractalkine</subject><subject>Gene Knockout Techniques</subject><subject>Genetic Vectors</subject><subject>Genomes</subject><subject>Humans</subject><subject>Immunoglobulin G</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>Internalization</subject><subject>Ligands</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Movement disorders</subject><subject>Multiple sclerosis</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neurons</subject><subject>Neurotoxicity</subject><subject>Neurotoxins</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - immunology</subject><subject>Parkinson's disease</subject><subject>Pathogenesis</subject><subject>Phagocytosis</subject><subject>Proteins</subject><subject>Receptors, Chemokine - genetics</subject><subject>Receptors, Chemokine - metabolism</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Substantia nigra</subject><subject>Synuclein</subject><subject>Therapeutic applications</subject><subject>Tumor necrosis factor-TNF</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Us1u1DAQjhCIlsIbILDEOYv_k1yQUKGwUhGIwtmaOOM0S9be2gnSPhYvwjPhdtOqPXDy2PP9jO2vKF4yumKiYm83YY4extUueFxRJqnS-lFxzBrBS82peHyvPiqepbShVIla66fFEddSN7yix0V_FsFOMP4aPJKLoc-Kg-_Jd-znESZMZLpEsvZuhO0WphD3uZWyZUIyeAKe_P1TXuz9bEfM-y-hw5EER75BzIopePJhSAgJnxdPHIwJXyzrSfHz7OOP08_l-ddP69P356VVXE-lZa1wFeUgO2u1E1JQy2qQDetyzWrZOoHOtQJlx62UEjINGRU1WI26EyfF64PubgzJLG-UDKs4l5Woa54R6wOiC7AxuzhsIe5NgMHcHITYG4jTkC9kVMc6ZSnjiqJUtWw0065uFerWts2N27vFbW632Fn0U4TxgejDjh8uTR9-G6lpxZTKAm8WgRiuZkzTf0aWB5SNIaWI7s6BUXMdhluWuQ6DWcKQaa_uT3dHuv198Q-QirTa</recordid><startdate>20151015</startdate><enddate>20151015</enddate><creator>Thome, Aaron D</creator><creator>Standaert, David G</creator><creator>Harms, Ashley S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20151015</creationdate><title>Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease</title><author>Thome, Aaron D ; Standaert, David G ; Harms, Ashley S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-c1b3f702a4dcc6f3430c18a491d343184bf3effb3e4d2c444a526e1038ac6e6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - metabolism</topic><topic>alpha-Synuclein - pharmacology</topic><topic>Alzheimer's disease</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antigens</topic><topic>Beads</topic><topic>Brain</topic><topic>Chemokine CX3CL1 - metabolism</topic><topic>CX3C Chemokine Receptor 1</topic><topic>CX3CR1 protein</topic><topic>Cytokines</topic><topic>Dependovirus - genetics</topic><topic>Disease Models, Animal</topic><topic>Dopamine</topic><topic>Dopamine receptors</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Fluorescence</topic><topic>Fractalkine</topic><topic>Gene Knockout Techniques</topic><topic>Genetic Vectors</topic><topic>Genomes</topic><topic>Humans</topic><topic>Immunoglobulin G</topic><topic>Inflammation</topic><topic>Inflammatory response</topic><topic>Internalization</topic><topic>Ligands</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Movement disorders</topic><topic>Multiple sclerosis</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Neurons</topic><topic>Neurotoxicity</topic><topic>Neurotoxins</topic><topic>Parkinson Disease - genetics</topic><topic>Parkinson Disease - immunology</topic><topic>Parkinson's disease</topic><topic>Pathogenesis</topic><topic>Phagocytosis</topic><topic>Proteins</topic><topic>Receptors, Chemokine - genetics</topic><topic>Receptors, Chemokine - metabolism</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Substantia nigra</topic><topic>Synuclein</topic><topic>Therapeutic applications</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thome, Aaron D</creatorcontrib><creatorcontrib>Standaert, David G</creatorcontrib><creatorcontrib>Harms, Ashley S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer's disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation.
To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn.
We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn.
Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26469270</pmid><doi>10.1371/journal.pone.0140566</doi><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Synuclein - genetics alpha-Synuclein - metabolism alpha-Synuclein - pharmacology Alzheimer's disease Animal models Animals Antigens Beads Brain Chemokine CX3CL1 - metabolism CX3C Chemokine Receptor 1 CX3CR1 protein Cytokines Dependovirus - genetics Disease Models, Animal Dopamine Dopamine receptors Dopaminergic Neurons - metabolism Fluorescence Fractalkine Gene Knockout Techniques Genetic Vectors Genomes Humans Immunoglobulin G Inflammation Inflammatory response Internalization Ligands Mice Microglia Microglia - drug effects Movement disorders Multiple sclerosis Neurodegeneration Neurodegenerative diseases Neurology Neurons Neurotoxicity Neurotoxins Parkinson Disease - genetics Parkinson Disease - immunology Parkinson's disease Pathogenesis Phagocytosis Proteins Receptors, Chemokine - genetics Receptors, Chemokine - metabolism Rodents Signal transduction Signaling Substantia nigra Synuclein Therapeutic applications Tumor necrosis factor-TNF |
| title | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
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