Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury
Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regula...
Gespeichert in:
| Veröffentlicht in: | Glia 2024-02, Vol.72 (2), p.411-432 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 432 |
|---|---|
| container_issue | 2 |
| container_start_page | 411 |
| container_title | Glia |
| container_volume | 72 |
| creator | Endo, Mitsuharu Tanaka, Yuki Fukuoka, Mayo Suzuki, Hayata Minami, Yasuhiro |
| description | Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
Main Points
bFGF and inflammatory cytokines cooperatively activate Wnt5a/Ror2‐Nrf2 axis in astrocytes.
Wnt5a/Ror2‐Nrf2 axis is activated in reactive astrocytes induced after brain hemorrhage and promotes repair of the damaged blood brain barrier. |
| doi_str_mv | 10.1002/glia.24483 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2884677153</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2900503664</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3603-f4ec90bebc990b701b52fb350f285fa3beae29fe03f6e90abcc8ad12ec8f0d6c3</originalsourceid><addsrcrecordid>eNp9kEtKBDEQhoMoOj42HkAa3IjQWkn6laWILxgURHEZ0pmKZOjpaJJWZucRPKMnMeOoCxeuqor66qf4CNmlcEQB2PFjZ9URK4qGr5ARBdHklPJqlYygEUVOC0E3yGYIUwCahnqdbPBaQFFRNiLyoY-lOr51nmVP3s1cxJBde8M-3t5nOLEq4iSLNoQBF_uIOtoXzMzQp8b1mTOZCtE7PV8cKhPRZ61Xts9sPx38fJusGdUF3PmuW-T-_Ozu9DIf31xcnZ6Mc80r4LkpUAtosdUilRpoWzLT8hIMa0qjeIsKmTAI3FQoQLVaN2pCGerGwKTSfIscLHPTk88DhihnNmjsOtWjG4JkTVNUdU1LntD9P-jUDb5P30kmAErgVVUk6nBJae9C8Gjkk7cz5eeSglxolwvt8kt7gve-I4c2WftFfzwngC6BV9vh_J8oeTG-OlmGfgKzQY92</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2900503664</pqid></control><display><type>article</type><title>Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Endo, Mitsuharu ; Tanaka, Yuki ; Fukuoka, Mayo ; Suzuki, Hayata ; Minami, Yasuhiro</creator><creatorcontrib>Endo, Mitsuharu ; Tanaka, Yuki ; Fukuoka, Mayo ; Suzuki, Hayata ; Minami, Yasuhiro</creatorcontrib><description>Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
Main Points
bFGF and inflammatory cytokines cooperatively activate Wnt5a/Ror2‐Nrf2 axis in astrocytes.
Wnt5a/Ror2‐Nrf2 axis is activated in reactive astrocytes induced after brain hemorrhage and promotes repair of the damaged blood brain barrier.</description><identifier>ISSN: 0894-1491</identifier><identifier>ISSN: 1098-1136</identifier><identifier>EISSN: 1098-1136</identifier><identifier>DOI: 10.1002/glia.24483</identifier><identifier>PMID: 37904612</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Animal models ; Animals ; Astrocytes ; Astrocytes - metabolism ; bFGF ; Blood-brain barrier ; Brain damage ; Brain Injuries - genetics ; Brain Injuries - metabolism ; Brain injury ; Collagenase ; Cytokines ; Cytokines - metabolism ; Fibroblast growth factor 2 ; Gene expression ; Glial cells ; Growth factors ; Head injuries ; Heme oxygenase (decyclizing) ; Hemin ; Hemoglobin ; Hemorrhage ; Inflammation ; Mice ; Molecular modelling ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Nrf2 ; oxidative stress ; reactive astrocytes ; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism ; Ror2 ; Signal Transduction ; Tissues ; Traumatic brain injury ; Wnt protein ; Wnt-5a Protein - metabolism ; Wnt5a</subject><ispartof>Glia, 2024-02, Vol.72 (2), p.411-432</ispartof><rights>2023 Wiley Periodicals LLC.</rights><rights>2024 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3603-f4ec90bebc990b701b52fb350f285fa3beae29fe03f6e90abcc8ad12ec8f0d6c3</cites><orcidid>0000-0001-6713-1732 ; 0000-0003-3514-4285</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.24483$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fglia.24483$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37904612$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Endo, Mitsuharu</creatorcontrib><creatorcontrib>Tanaka, Yuki</creatorcontrib><creatorcontrib>Fukuoka, Mayo</creatorcontrib><creatorcontrib>Suzuki, Hayata</creatorcontrib><creatorcontrib>Minami, Yasuhiro</creatorcontrib><title>Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury</title><title>Glia</title><addtitle>Glia</addtitle><description>Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
Main Points
bFGF and inflammatory cytokines cooperatively activate Wnt5a/Ror2‐Nrf2 axis in astrocytes.
Wnt5a/Ror2‐Nrf2 axis is activated in reactive astrocytes induced after brain hemorrhage and promotes repair of the damaged blood brain barrier.</description><subject>Animal models</subject><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>bFGF</subject><subject>Blood-brain barrier</subject><subject>Brain damage</subject><subject>Brain Injuries - genetics</subject><subject>Brain Injuries - metabolism</subject><subject>Brain injury</subject><subject>Collagenase</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Fibroblast growth factor 2</subject><subject>Gene expression</subject><subject>Glial cells</subject><subject>Growth factors</subject><subject>Head injuries</subject><subject>Heme oxygenase (decyclizing)</subject><subject>Hemin</subject><subject>Hemoglobin</subject><subject>Hemorrhage</subject><subject>Inflammation</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nrf2</subject><subject>oxidative stress</subject><subject>reactive astrocytes</subject><subject>Receptor Tyrosine Kinase-like Orphan Receptors - metabolism</subject><subject>Ror2</subject><subject>Signal Transduction</subject><subject>Tissues</subject><subject>Traumatic brain injury</subject><subject>Wnt protein</subject><subject>Wnt-5a Protein - metabolism</subject><subject>Wnt5a</subject><issn>0894-1491</issn><issn>1098-1136</issn><issn>1098-1136</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtKBDEQhoMoOj42HkAa3IjQWkn6laWILxgURHEZ0pmKZOjpaJJWZucRPKMnMeOoCxeuqor66qf4CNmlcEQB2PFjZ9URK4qGr5ARBdHklPJqlYygEUVOC0E3yGYIUwCahnqdbPBaQFFRNiLyoY-lOr51nmVP3s1cxJBde8M-3t5nOLEq4iSLNoQBF_uIOtoXzMzQp8b1mTOZCtE7PV8cKhPRZ61Xts9sPx38fJusGdUF3PmuW-T-_Ozu9DIf31xcnZ6Mc80r4LkpUAtosdUilRpoWzLT8hIMa0qjeIsKmTAI3FQoQLVaN2pCGerGwKTSfIscLHPTk88DhihnNmjsOtWjG4JkTVNUdU1LntD9P-jUDb5P30kmAErgVVUk6nBJae9C8Gjkk7cz5eeSglxolwvt8kt7gve-I4c2WftFfzwngC6BV9vh_J8oeTG-OlmGfgKzQY92</recordid><startdate>202402</startdate><enddate>202402</enddate><creator>Endo, Mitsuharu</creator><creator>Tanaka, Yuki</creator><creator>Fukuoka, Mayo</creator><creator>Suzuki, Hayata</creator><creator>Minami, Yasuhiro</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</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>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><orcidid>https://orcid.org/0000-0001-6713-1732</orcidid><orcidid>https://orcid.org/0000-0003-3514-4285</orcidid></search><sort><creationdate>202402</creationdate><title>Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury</title><author>Endo, Mitsuharu ; Tanaka, Yuki ; Fukuoka, Mayo ; Suzuki, Hayata ; Minami, Yasuhiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3603-f4ec90bebc990b701b52fb350f285fa3beae29fe03f6e90abcc8ad12ec8f0d6c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Astrocytes</topic><topic>Astrocytes - metabolism</topic><topic>bFGF</topic><topic>Blood-brain barrier</topic><topic>Brain damage</topic><topic>Brain Injuries - genetics</topic><topic>Brain Injuries - metabolism</topic><topic>Brain injury</topic><topic>Collagenase</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Fibroblast growth factor 2</topic><topic>Gene expression</topic><topic>Glial cells</topic><topic>Growth factors</topic><topic>Head injuries</topic><topic>Heme oxygenase (decyclizing)</topic><topic>Hemin</topic><topic>Hemoglobin</topic><topic>Hemorrhage</topic><topic>Inflammation</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nrf2</topic><topic>oxidative stress</topic><topic>reactive astrocytes</topic><topic>Receptor Tyrosine Kinase-like Orphan Receptors - metabolism</topic><topic>Ror2</topic><topic>Signal Transduction</topic><topic>Tissues</topic><topic>Traumatic brain injury</topic><topic>Wnt protein</topic><topic>Wnt-5a Protein - metabolism</topic><topic>Wnt5a</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Endo, Mitsuharu</creatorcontrib><creatorcontrib>Tanaka, Yuki</creatorcontrib><creatorcontrib>Fukuoka, Mayo</creatorcontrib><creatorcontrib>Suzuki, Hayata</creatorcontrib><creatorcontrib>Minami, Yasuhiro</creatorcontrib><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><jtitle>Glia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Endo, Mitsuharu</au><au>Tanaka, Yuki</au><au>Fukuoka, Mayo</au><au>Suzuki, Hayata</au><au>Minami, Yasuhiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury</atitle><jtitle>Glia</jtitle><addtitle>Glia</addtitle><date>2024-02</date><risdate>2024</risdate><volume>72</volume><issue>2</issue><spage>411</spage><epage>432</epage><pages>411-432</pages><issn>0894-1491</issn><issn>1098-1136</issn><eissn>1098-1136</eissn><abstract>Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
Main Points
bFGF and inflammatory cytokines cooperatively activate Wnt5a/Ror2‐Nrf2 axis in astrocytes.
Wnt5a/Ror2‐Nrf2 axis is activated in reactive astrocytes induced after brain hemorrhage and promotes repair of the damaged blood brain barrier.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>37904612</pmid><doi>10.1002/glia.24483</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0001-6713-1732</orcidid><orcidid>https://orcid.org/0000-0003-3514-4285</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0894-1491 |
| ispartof | Glia, 2024-02, Vol.72 (2), p.411-432 |
| issn | 0894-1491 1098-1136 1098-1136 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2884677153 |
| source | MEDLINE; Access via Wiley Online Library |
| subjects | Animal models Animals Astrocytes Astrocytes - metabolism bFGF Blood-brain barrier Brain damage Brain Injuries - genetics Brain Injuries - metabolism Brain injury Collagenase Cytokines Cytokines - metabolism Fibroblast growth factor 2 Gene expression Glial cells Growth factors Head injuries Heme oxygenase (decyclizing) Hemin Hemoglobin Hemorrhage Inflammation Mice Molecular modelling NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Nrf2 oxidative stress reactive astrocytes Receptor Tyrosine Kinase-like Orphan Receptors - metabolism Ror2 Signal Transduction Tissues Traumatic brain injury Wnt protein Wnt-5a Protein - metabolism Wnt5a |
| title | Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T20%3A43%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Wnt5a/Ror2%20promotes%20Nrf2%E2%80%90mediated%20tissue%20protective%20function%20of%20astrocytes%20after%20brain%20injury&rft.jtitle=Glia&rft.au=Endo,%20Mitsuharu&rft.date=2024-02&rft.volume=72&rft.issue=2&rft.spage=411&rft.epage=432&rft.pages=411-432&rft.issn=0894-1491&rft.eissn=1098-1136&rft_id=info:doi/10.1002/glia.24483&rft_dat=%3Cproquest_cross%3E2900503664%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2900503664&rft_id=info:pmid/37904612&rfr_iscdi=true |