TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown
Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-tran...
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| Veröffentlicht in: | Experimental eye research 2021-01, Vol.202, p.108292-108292, Article 108292 |
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| creator | Valença, Andreia Mendes-Jorge, Luísa Bonet, Aina Catita, Joana Ramos, David Jose-Cunilleras, Eduard Garcia, Miguel Carretero, Ana Nacher, Victor Navarro, Marc Ruberte, Jesús |
| description | Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.
•TIM2, a receptor for H-ferritin, is present in the mouse retina.•TIM2 deficiency induces Scara5 overexpression, ferritin accumulation, and iron overload in the retina.•TIM2 deficiency leads to BRB breakdown and retinal edema. |
| doi_str_mv | 10.1016/j.exer.2020.108292 |
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•TIM2, a receptor for H-ferritin, is present in the mouse retina.•TIM2 deficiency induces Scara5 overexpression, ferritin accumulation, and iron overload in the retina.•TIM2 deficiency leads to BRB breakdown and retinal edema.</description><identifier>ISSN: 0014-4835</identifier><identifier>EISSN: 1096-0007</identifier><identifier>DOI: 10.1016/j.exer.2020.108292</identifier><identifier>PMID: 33065090</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Biological Transport ; Blood-Retinal Barrier - physiology ; Blotting, Western ; BRB breakdown ; Ependymoglial Cells - metabolism ; Ferritins - metabolism ; Homeostasis - physiology ; Immunohistochemistry ; Iron overload ; Membrane Proteins - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Electron, Transmission ; Ophthalmoscopy ; Oxidative Stress ; Reactive Oxygen Species - metabolism ; Real-Time Polymerase Chain Reaction ; Retinal edema ; Scara5 ; Scavenger Receptors, Class A - metabolism ; Spectrometry, X-Ray Emission ; Tandem Mass Spectrometry ; TIM2 ; Vascular Endothelial Growth Factor A - metabolism ; VEGF overexpression</subject><ispartof>Experimental eye research, 2021-01, Vol.202, p.108292-108292, Article 108292</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-deb6ac9960277743458669a7ee9719aa9a52c1d7b69058fb4b312c675cc0b483</citedby><cites>FETCH-LOGICAL-c356t-deb6ac9960277743458669a7ee9719aa9a52c1d7b69058fb4b312c675cc0b483</cites><orcidid>0000-0001-6000-2970</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.exer.2020.108292$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33065090$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Valença, Andreia</creatorcontrib><creatorcontrib>Mendes-Jorge, Luísa</creatorcontrib><creatorcontrib>Bonet, Aina</creatorcontrib><creatorcontrib>Catita, Joana</creatorcontrib><creatorcontrib>Ramos, David</creatorcontrib><creatorcontrib>Jose-Cunilleras, Eduard</creatorcontrib><creatorcontrib>Garcia, Miguel</creatorcontrib><creatorcontrib>Carretero, Ana</creatorcontrib><creatorcontrib>Nacher, Victor</creatorcontrib><creatorcontrib>Navarro, Marc</creatorcontrib><creatorcontrib>Ruberte, Jesús</creatorcontrib><title>TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown</title><title>Experimental eye research</title><addtitle>Exp Eye Res</addtitle><description>Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.
•TIM2, a receptor for H-ferritin, is present in the mouse retina.•TIM2 deficiency induces Scara5 overexpression, ferritin accumulation, and iron overload in the retina.•TIM2 deficiency leads to BRB breakdown and retinal edema.</description><subject>Animals</subject><subject>Biological Transport</subject><subject>Blood-Retinal Barrier - physiology</subject><subject>Blotting, Western</subject><subject>BRB breakdown</subject><subject>Ependymoglial Cells - metabolism</subject><subject>Ferritins - metabolism</subject><subject>Homeostasis - physiology</subject><subject>Immunohistochemistry</subject><subject>Iron overload</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microscopy, Electron, Transmission</subject><subject>Ophthalmoscopy</subject><subject>Oxidative Stress</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Retinal edema</subject><subject>Scara5</subject><subject>Scavenger Receptors, Class A - metabolism</subject><subject>Spectrometry, X-Ray Emission</subject><subject>Tandem Mass Spectrometry</subject><subject>TIM2</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>VEGF overexpression</subject><issn>0014-4835</issn><issn>1096-0007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LAzEQhoMoWqt_wIPk6GVrks0mG_AixY-C4qWeQz6mkJpuNNlW_fduafXoaYbheV-YB6ELSiaUUHG9nMAX5AkjbHtomWIHaESJEhUhRB6iESGUV7ytmxN0WspyuNZc8mN0UtdENESREXqdz54ZXiW_jqaHgjP0oTMRh5w6HGEDsWDTeRwKDt0mxQ0Me4dtTMlXv7A1OQfI2GYwbz59dmfoaGFigfP9HKP5_d18-lg9vTzMprdPlasb0VcerDBOKUGYlJLXvGmFUEYCKEmVMco0zFEvrVCkaReW25oyJ2TjHLHDX2N0tat9z-ljDaXXq1AcxGg6SOuiGW9oyyVjfEDZDnU5lZJhod9zWJn8rSnRW5t6qbc29dam3tkcQpf7_rVdgf-L_OobgJsdMGiCzaBAFxegc-BDBtdrn8J__T9Db4Va</recordid><startdate>202101</startdate><enddate>202101</enddate><creator>Valença, Andreia</creator><creator>Mendes-Jorge, Luísa</creator><creator>Bonet, Aina</creator><creator>Catita, Joana</creator><creator>Ramos, David</creator><creator>Jose-Cunilleras, Eduard</creator><creator>Garcia, Miguel</creator><creator>Carretero, Ana</creator><creator>Nacher, Victor</creator><creator>Navarro, Marc</creator><creator>Ruberte, Jesús</creator><general>Elsevier Ltd</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>7X8</scope><orcidid>https://orcid.org/0000-0001-6000-2970</orcidid></search><sort><creationdate>202101</creationdate><title>TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown</title><author>Valença, Andreia ; Mendes-Jorge, Luísa ; Bonet, Aina ; Catita, Joana ; Ramos, David ; Jose-Cunilleras, Eduard ; Garcia, Miguel ; Carretero, Ana ; Nacher, Victor ; Navarro, Marc ; Ruberte, Jesús</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-deb6ac9960277743458669a7ee9719aa9a52c1d7b69058fb4b312c675cc0b483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Biological Transport</topic><topic>Blood-Retinal Barrier - physiology</topic><topic>Blotting, Western</topic><topic>BRB breakdown</topic><topic>Ependymoglial Cells - metabolism</topic><topic>Ferritins - metabolism</topic><topic>Homeostasis - physiology</topic><topic>Immunohistochemistry</topic><topic>Iron overload</topic><topic>Membrane Proteins - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microscopy, Electron, Transmission</topic><topic>Ophthalmoscopy</topic><topic>Oxidative Stress</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Retinal edema</topic><topic>Scara5</topic><topic>Scavenger Receptors, Class A - metabolism</topic><topic>Spectrometry, X-Ray Emission</topic><topic>Tandem Mass Spectrometry</topic><topic>TIM2</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>VEGF overexpression</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valença, Andreia</creatorcontrib><creatorcontrib>Mendes-Jorge, Luísa</creatorcontrib><creatorcontrib>Bonet, Aina</creatorcontrib><creatorcontrib>Catita, Joana</creatorcontrib><creatorcontrib>Ramos, David</creatorcontrib><creatorcontrib>Jose-Cunilleras, Eduard</creatorcontrib><creatorcontrib>Garcia, Miguel</creatorcontrib><creatorcontrib>Carretero, Ana</creatorcontrib><creatorcontrib>Nacher, Victor</creatorcontrib><creatorcontrib>Navarro, Marc</creatorcontrib><creatorcontrib>Ruberte, Jesús</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental eye research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valença, Andreia</au><au>Mendes-Jorge, Luísa</au><au>Bonet, Aina</au><au>Catita, Joana</au><au>Ramos, David</au><au>Jose-Cunilleras, Eduard</au><au>Garcia, Miguel</au><au>Carretero, Ana</au><au>Nacher, Victor</au><au>Navarro, Marc</au><au>Ruberte, Jesús</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown</atitle><jtitle>Experimental eye research</jtitle><addtitle>Exp Eye Res</addtitle><date>2021-01</date><risdate>2021</risdate><volume>202</volume><spage>108292</spage><epage>108292</epage><pages>108292-108292</pages><artnum>108292</artnum><issn>0014-4835</issn><eissn>1096-0007</eissn><abstract>Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.
•TIM2, a receptor for H-ferritin, is present in the mouse retina.•TIM2 deficiency induces Scara5 overexpression, ferritin accumulation, and iron overload in the retina.•TIM2 deficiency leads to BRB breakdown and retinal edema.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33065090</pmid><doi>10.1016/j.exer.2020.108292</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-6000-2970</orcidid></addata></record> |
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| subjects | Animals Biological Transport Blood-Retinal Barrier - physiology Blotting, Western BRB breakdown Ependymoglial Cells - metabolism Ferritins - metabolism Homeostasis - physiology Immunohistochemistry Iron overload Membrane Proteins - physiology Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Electron, Transmission Ophthalmoscopy Oxidative Stress Reactive Oxygen Species - metabolism Real-Time Polymerase Chain Reaction Retinal edema Scara5 Scavenger Receptors, Class A - metabolism Spectrometry, X-Ray Emission Tandem Mass Spectrometry TIM2 Vascular Endothelial Growth Factor A - metabolism VEGF overexpression |
| title | TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown |
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