Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia
Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation...
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creator | Pannell, Maria Economopoulos, Vasiliki Wilson, Thomas C. Kersemans, Veerle Isenegger, Patrick G. Larkin, James R. Smart, Sean Gilchrist, Stuart Gouverneur, Véronique Sibson, Nicola R. |
description | Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited to a specific inflammatory phenotype. TSPO upregulation was assessed by flow cytometry in cultured astrocytes, microglia, and macrophages stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin‐4 (Il‐4). Subsequently, mice were injected intracerebrally with either a TNF‐inducing adenovirus (AdTNF) or IL‐4. Glial expression of TSPO and pro‐/anti‐inflammatory markers was assessed by immunohistochemistry/fluorescence and flow cytometry. Finally, AdTNF or IL‐4 injected mice underwent PET imaging with injection of the TSPO radioligand 18F‐DPA‐713, followed by ex vivo autoradiography. TSPO expression was significantly increased in pro‐inflammatory microglia/macrophages and astrocytes both in vitro, and in vivo after AdTNF injection (p |
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Main points
TSPO expression is strongly associated with pro‐ but not anti‐inflammatory microglia, macrophages and astrocytes, in vitro and in vivo.
PET imaging with TSPO ligand 18F‐DPA‐713 reveals the pro‐inflammatory population of glial cells.</description><identifier>ISSN: 0894-1491</identifier><identifier>ISSN: 1098-1136</identifier><identifier>EISSN: 1098-1136</identifier><identifier>DOI: 10.1002/glia.23716</identifier><identifier>PMID: 31479168</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Animals ; Astrocytes ; Astrocytes - drug effects ; Astrocytes - metabolism ; Autoradiography ; Binding ; brain inflammation ; Carrier Proteins - metabolism ; Disease Models, Animal ; Flow cytometry ; Fluorescence ; Fluorine isotopes ; Genotype & phenotype ; Glial cells ; Immunohistochemistry ; In vivo methods and tests ; Inflammation ; Inflammation - drug therapy ; Inflammation - metabolism ; Injection ; Interleukins ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Macrophages ; Macrophages - drug effects ; Macrophages - metabolism ; Markers ; Medical imaging ; Mice ; Microglia ; Microglia - drug effects ; Microglia - metabolism ; Neuroglia - drug effects ; Neuroglia - metabolism ; Neuroimaging ; Neurological diseases ; Neuronal-glial interactions ; PET ; Phenotypes ; Positron emission ; Positron emission tomography ; Positron-Emission Tomography - methods ; Proteins ; Tomography ; translocator protein ; Tumor necrosis factor ; Tumor necrosis factor-TNF ; Up-regulation</subject><ispartof>Glia, 2020-02, Vol.68 (2), p.280-297</ispartof><rights>2019 The Authors. published by Wiley Periodicals, Inc.</rights><rights>2019 The Authors. Glia published by Wiley Periodicals, Inc.</rights><rights>2019. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5146-f6e357c654472ed7c3e2ee804368963464a13e10cabd7fb7314baf9abf6ca6f03</citedby><cites>FETCH-LOGICAL-c5146-f6e357c654472ed7c3e2ee804368963464a13e10cabd7fb7314baf9abf6ca6f03</cites><orcidid>0000-0002-7764-5574</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fglia.23716$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fglia.23716$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,781,785,886,1418,27926,27927,45576,45577</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31479168$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pannell, Maria</creatorcontrib><creatorcontrib>Economopoulos, Vasiliki</creatorcontrib><creatorcontrib>Wilson, Thomas C.</creatorcontrib><creatorcontrib>Kersemans, Veerle</creatorcontrib><creatorcontrib>Isenegger, Patrick G.</creatorcontrib><creatorcontrib>Larkin, James R.</creatorcontrib><creatorcontrib>Smart, Sean</creatorcontrib><creatorcontrib>Gilchrist, Stuart</creatorcontrib><creatorcontrib>Gouverneur, Véronique</creatorcontrib><creatorcontrib>Sibson, Nicola R.</creatorcontrib><title>Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia</title><title>Glia</title><addtitle>Glia</addtitle><description>Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited to a specific inflammatory phenotype. TSPO upregulation was assessed by flow cytometry in cultured astrocytes, microglia, and macrophages stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin‐4 (Il‐4). Subsequently, mice were injected intracerebrally with either a TNF‐inducing adenovirus (AdTNF) or IL‐4. Glial expression of TSPO and pro‐/anti‐inflammatory markers was assessed by immunohistochemistry/fluorescence and flow cytometry. Finally, AdTNF or IL‐4 injected mice underwent PET imaging with injection of the TSPO radioligand 18F‐DPA‐713, followed by ex vivo autoradiography. TSPO expression was significantly increased in pro‐inflammatory microglia/macrophages and astrocytes both in vitro, and in vivo after AdTNF injection (p < .001 vs. control hemisphere), determined both histologically and by FACS. Both PET imaging and autoradiography revealed a significant (p < .001) increase in 18F‐DPA‐713 binding in the ipsilateral hemisphere of AdTNF‐injected mice. In contrast, no increase in either TSPO expression assessed histologically and by FACS, or ligand binding by PET/autoradiography was observed after IL‐4 injection. Taken together, these results suggest that TSPO imaging specifically reveals the pro‐inflammatory population of activated glial cells in the brain in response to inflammatory stimuli. Since the inflammatory phenotype of glial cells is critical to their role in neurological disease, these findings may enhance the utility and application of TSPO imaging.
Main points
TSPO expression is strongly associated with pro‐ but not anti‐inflammatory microglia, macrophages and astrocytes, in vitro and in vivo.
PET imaging with TSPO ligand 18F‐DPA‐713 reveals the pro‐inflammatory population of glial cells.</description><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - metabolism</subject><subject>Autoradiography</subject><subject>Binding</subject><subject>brain inflammation</subject><subject>Carrier Proteins - metabolism</subject><subject>Disease Models, Animal</subject><subject>Flow cytometry</subject><subject>Fluorescence</subject><subject>Fluorine isotopes</subject><subject>Genotype & phenotype</subject><subject>Glial cells</subject><subject>Immunohistochemistry</subject><subject>In vivo methods and tests</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - metabolism</subject><subject>Injection</subject><subject>Interleukins</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Markers</subject><subject>Medical imaging</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - metabolism</subject><subject>Neuroglia - drug effects</subject><subject>Neuroglia - metabolism</subject><subject>Neuroimaging</subject><subject>Neurological diseases</subject><subject>Neuronal-glial interactions</subject><subject>PET</subject><subject>Phenotypes</subject><subject>Positron emission</subject><subject>Positron emission tomography</subject><subject>Positron-Emission Tomography - methods</subject><subject>Proteins</subject><subject>Tomography</subject><subject>translocator protein</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor-TNF</subject><subject>Up-regulation</subject><issn>0894-1491</issn><issn>1098-1136</issn><issn>1098-1136</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1qFTEYhoMo9ljdeAEScCPC1PydzMxGKKXWAwfc6DpkMl_GlEwyJjOV48pL6DV6JeY4tagLVyHkycv7g9BzSs4oIezN4J0-Y7ym8gHaUNI2FaVcPkQb0rSioqKlJ-hJzteE0HKpH6MTTkXdUtlsUN6NenBhwNHiOemQfTR6jglPKc7gAl6mBMPi9exiwC7jDB7M7G4A25X68f3WBev1OB7_HfAUvU7uG_RY5zlFc5ghYx16PDqT4tHrU_TIap_h2d15ij69u_x48b7af7jaXZzvK7OlQlZWAt_WRm6FqBn0teHAABoiuGxayYUUmnKgxOiur21Xl1Cdtq3urDRaWsJP0dtVd1q6EXoDoST0akpu1Omgonbq75fgPqsh3ihZumFtUwRe3Qmk-GWBPKvRZQPe6wBxyYqxhretLHhBX_6DXsclhRJPMc6o5FveyEK9XqnSRM4J7L0ZStRxS3XsR_3assAv_rR_j_4erwB0Bb46D4f_SKmr_e58Ff0JBF6udQ</recordid><startdate>202002</startdate><enddate>202002</enddate><creator>Pannell, Maria</creator><creator>Economopoulos, Vasiliki</creator><creator>Wilson, Thomas C.</creator><creator>Kersemans, Veerle</creator><creator>Isenegger, Patrick G.</creator><creator>Larkin, James R.</creator><creator>Smart, Sean</creator><creator>Gilchrist, Stuart</creator><creator>Gouverneur, Véronique</creator><creator>Sibson, Nicola R.</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><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>7QL</scope><scope>7T7</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7764-5574</orcidid></search><sort><creationdate>202002</creationdate><title>Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia</title><author>Pannell, Maria ; Economopoulos, Vasiliki ; Wilson, Thomas C. ; Kersemans, Veerle ; Isenegger, Patrick G. ; Larkin, James R. ; Smart, Sean ; Gilchrist, Stuart ; Gouverneur, Véronique ; Sibson, Nicola R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5146-f6e357c654472ed7c3e2ee804368963464a13e10cabd7fb7314baf9abf6ca6f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Astrocytes</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - metabolism</topic><topic>Autoradiography</topic><topic>Binding</topic><topic>brain inflammation</topic><topic>Carrier Proteins - metabolism</topic><topic>Disease Models, Animal</topic><topic>Flow cytometry</topic><topic>Fluorescence</topic><topic>Fluorine isotopes</topic><topic>Genotype & phenotype</topic><topic>Glial cells</topic><topic>Immunohistochemistry</topic><topic>In vivo methods and tests</topic><topic>Inflammation</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - metabolism</topic><topic>Injection</topic><topic>Interleukins</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Markers</topic><topic>Medical imaging</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Microglia - metabolism</topic><topic>Neuroglia - drug effects</topic><topic>Neuroglia - metabolism</topic><topic>Neuroimaging</topic><topic>Neurological diseases</topic><topic>Neuronal-glial interactions</topic><topic>PET</topic><topic>Phenotypes</topic><topic>Positron emission</topic><topic>Positron emission tomography</topic><topic>Positron-Emission Tomography - methods</topic><topic>Proteins</topic><topic>Tomography</topic><topic>translocator protein</topic><topic>Tumor necrosis factor</topic><topic>Tumor necrosis factor-TNF</topic><topic>Up-regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pannell, Maria</creatorcontrib><creatorcontrib>Economopoulos, Vasiliki</creatorcontrib><creatorcontrib>Wilson, Thomas C.</creatorcontrib><creatorcontrib>Kersemans, Veerle</creatorcontrib><creatorcontrib>Isenegger, Patrick G.</creatorcontrib><creatorcontrib>Larkin, James R.</creatorcontrib><creatorcontrib>Smart, Sean</creatorcontrib><creatorcontrib>Gilchrist, Stuart</creatorcontrib><creatorcontrib>Gouverneur, Véronique</creatorcontrib><creatorcontrib>Sibson, Nicola R.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Glia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pannell, Maria</au><au>Economopoulos, Vasiliki</au><au>Wilson, Thomas C.</au><au>Kersemans, Veerle</au><au>Isenegger, Patrick G.</au><au>Larkin, James R.</au><au>Smart, Sean</au><au>Gilchrist, Stuart</au><au>Gouverneur, Véronique</au><au>Sibson, Nicola R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia</atitle><jtitle>Glia</jtitle><addtitle>Glia</addtitle><date>2020-02</date><risdate>2020</risdate><volume>68</volume><issue>2</issue><spage>280</spage><epage>297</epage><pages>280-297</pages><issn>0894-1491</issn><issn>1098-1136</issn><eissn>1098-1136</eissn><abstract>Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited to a specific inflammatory phenotype. TSPO upregulation was assessed by flow cytometry in cultured astrocytes, microglia, and macrophages stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin‐4 (Il‐4). Subsequently, mice were injected intracerebrally with either a TNF‐inducing adenovirus (AdTNF) or IL‐4. Glial expression of TSPO and pro‐/anti‐inflammatory markers was assessed by immunohistochemistry/fluorescence and flow cytometry. Finally, AdTNF or IL‐4 injected mice underwent PET imaging with injection of the TSPO radioligand 18F‐DPA‐713, followed by ex vivo autoradiography. TSPO expression was significantly increased in pro‐inflammatory microglia/macrophages and astrocytes both in vitro, and in vivo after AdTNF injection (p < .001 vs. control hemisphere), determined both histologically and by FACS. Both PET imaging and autoradiography revealed a significant (p < .001) increase in 18F‐DPA‐713 binding in the ipsilateral hemisphere of AdTNF‐injected mice. In contrast, no increase in either TSPO expression assessed histologically and by FACS, or ligand binding by PET/autoradiography was observed after IL‐4 injection. Taken together, these results suggest that TSPO imaging specifically reveals the pro‐inflammatory population of activated glial cells in the brain in response to inflammatory stimuli. Since the inflammatory phenotype of glial cells is critical to their role in neurological disease, these findings may enhance the utility and application of TSPO imaging.
Main points
TSPO expression is strongly associated with pro‐ but not anti‐inflammatory microglia, macrophages and astrocytes, in vitro and in vivo.
PET imaging with TSPO ligand 18F‐DPA‐713 reveals the pro‐inflammatory population of glial cells.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>31479168</pmid><doi>10.1002/glia.23716</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-7764-5574</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Astrocytes Astrocytes - drug effects Astrocytes - metabolism Autoradiography Binding brain inflammation Carrier Proteins - metabolism Disease Models, Animal Flow cytometry Fluorescence Fluorine isotopes Genotype & phenotype Glial cells Immunohistochemistry In vivo methods and tests Inflammation Inflammation - drug therapy Inflammation - metabolism Injection Interleukins Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophages Macrophages - drug effects Macrophages - metabolism Markers Medical imaging Mice Microglia Microglia - drug effects Microglia - metabolism Neuroglia - drug effects Neuroglia - metabolism Neuroimaging Neurological diseases Neuronal-glial interactions PET Phenotypes Positron emission Positron emission tomography Positron-Emission Tomography - methods Proteins Tomography translocator protein Tumor necrosis factor Tumor necrosis factor-TNF Up-regulation |
title | Imaging of translocator protein upregulation is selective for pro‐inflammatory polarized astrocytes and microglia |
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