Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis
Autoimmune uveitis is a relapsing blind-causing ocular condition with complex pathogenesis that is not completely understood. There is a high demand for accurate animal models of experimental autoimmune uveitis (EAU) suitable for elucidating the molecular mechanisms of the disease and testing new th...
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| Veröffentlicht in: | International journal of molecular sciences 2024-12, Vol.25 (23), p.12910 |
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| creator | Chistyakov, Dmitry V Tiulina, Veronika V Gancharova, Olga S Baksheeva, Viktoriia E Goriainov, Sergei V Shebardina, Natalia G Ivlev, Vasily A Komarov, Sergey V Shevelyova, Marina P Tikhomirova, Natalia K Philippov, Pavel P Vasil'ev, Vasiliy G Sergeeva, Marina G Permyakov, Sergei E Iomdina, Elena N Tsvetkov, Philipp O Senin, Ivan I Zernii, Evgeni Yu |
| description | Autoimmune uveitis is a relapsing blind-causing ocular condition with complex pathogenesis that is not completely understood. There is a high demand for accurate animal models of experimental autoimmune uveitis (EAU) suitable for elucidating the molecular mechanisms of the disease and testing new therapeutic approaches. Here, we demonstrated that photoreceptor Ca
/Zn
-sensor protein recoverin is a uveoretinal antigen in albino rabbits provoking typical autoimmune chorioretinitis 2-4 weeks after immunization. The pathologic process in recoverin-induced EAU shared features with human disease and included lymphocytic infiltration of the retina, Dalen-Fuchs nodules and foci of subtotal or total retinal atrophy, manifested as a decrease in amplitude of the a-wave of the electroretinogram. In some cases, changes in the retinal vascular pattern and subretinal hemorrhages were also observed. These signs were accompanied by a gradual accumulation of serum antibodies against recoverin. Biochemical examination of the aqueous humor (AH) revealed typical characteristics of inflammation and oxidative stress, including increased levels of TNF-α and IL-6 and decreased levels of IL-10, as well as decreased total antioxidant activity, superoxide dismutase and glutathione peroxidase activities, and increased zinc concentration. Consistently, metabolomic and targeted lipidomic analysis of AH showed high lactate and low ascorbic acid levels in early EAU; increased levels of key pro-inflammatory signaling lipids such as PGE2, TXB2, 11-HETE and Lyso-PAF; and reduced levels of the anti-inflammatory fatty acid DHA in advanced stages of the disease. Uveitic AH became enriched with recoverin, confirming disruption of the blood-ocular barrier and photoreceptor damage. Notably, the application of mitochondria-targeted antioxidant therapy impeded EAU progression by maintaining local antioxidant activity and suppressing TNF-α, IL-6 and PGE2 signaling. Overall, our results demonstrate that recoverin-induced EAU in rabbits represents an accurate model of human autoimmune posterior uveitis and suggest new directions for its therapy that can be trialed using the developed model. |
| doi_str_mv | 10.3390/ijms252312910 |
| format | Article |
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/Zn
-sensor protein recoverin is a uveoretinal antigen in albino rabbits provoking typical autoimmune chorioretinitis 2-4 weeks after immunization. The pathologic process in recoverin-induced EAU shared features with human disease and included lymphocytic infiltration of the retina, Dalen-Fuchs nodules and foci of subtotal or total retinal atrophy, manifested as a decrease in amplitude of the a-wave of the electroretinogram. In some cases, changes in the retinal vascular pattern and subretinal hemorrhages were also observed. These signs were accompanied by a gradual accumulation of serum antibodies against recoverin. Biochemical examination of the aqueous humor (AH) revealed typical characteristics of inflammation and oxidative stress, including increased levels of TNF-α and IL-6 and decreased levels of IL-10, as well as decreased total antioxidant activity, superoxide dismutase and glutathione peroxidase activities, and increased zinc concentration. Consistently, metabolomic and targeted lipidomic analysis of AH showed high lactate and low ascorbic acid levels in early EAU; increased levels of key pro-inflammatory signaling lipids such as PGE2, TXB2, 11-HETE and Lyso-PAF; and reduced levels of the anti-inflammatory fatty acid DHA in advanced stages of the disease. Uveitic AH became enriched with recoverin, confirming disruption of the blood-ocular barrier and photoreceptor damage. Notably, the application of mitochondria-targeted antioxidant therapy impeded EAU progression by maintaining local antioxidant activity and suppressing TNF-α, IL-6 and PGE2 signaling. Overall, our results demonstrate that recoverin-induced EAU in rabbits represents an accurate model of human autoimmune posterior uveitis and suggest new directions for its therapy that can be trialed using the developed model.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>EISSN: 1661-6596</identifier><identifier>DOI: 10.3390/ijms252312910</identifier><identifier>PMID: 39684616</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Albinism ; Amino acids ; Analysis ; Animals ; Antibodies ; Antigens ; Autoimmune Diseases ; Autoimmune Diseases - immunology ; Autoimmune Diseases - metabolism ; Autoimmune Diseases - pathology ; B cells ; Cytokines ; Disease ; Disease Models, Animal ; Edema ; Fatty acids ; Health aspects ; Inflammation ; Inflammation - metabolism ; Lactates ; Life Sciences ; Lymphocytes ; Organic compounds ; Oxidative Stress ; Photoreceptors ; Prostaglandins E ; Proteins ; Rabbits ; Retina ; Retina - metabolism ; Retina - pathology ; Retinal detachment ; Thymus gland ; Uveitis ; Uveitis - drug therapy ; Uveitis - immunology ; Uveitis - metabolism ; Uveitis - pathology ; Viral antibodies</subject><ispartof>International journal of molecular sciences, 2024-12, Vol.25 (23), p.12910</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c308t-5f5b8ba4ac1fbd0965b5f3cebeaebce246c68fe3bef95b9fd5245fd65330d6463</cites><orcidid>0000-0001-8143-3606 ; 0000-0002-7625-9110 ; 0000-0003-4086-3137 ; 0000-0003-0137-8585 ; 0009-0004-7638-5143 ; 0000-0002-8622-8836 ; 0000-0001-9664-9506 ; 0000-0002-3013-7863 ; 0000-0002-7764-693X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39684616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://amu.hal.science/hal-04893439$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Chistyakov, Dmitry V</creatorcontrib><creatorcontrib>Tiulina, Veronika V</creatorcontrib><creatorcontrib>Gancharova, Olga S</creatorcontrib><creatorcontrib>Baksheeva, Viktoriia E</creatorcontrib><creatorcontrib>Goriainov, Sergei V</creatorcontrib><creatorcontrib>Shebardina, Natalia G</creatorcontrib><creatorcontrib>Ivlev, Vasily A</creatorcontrib><creatorcontrib>Komarov, Sergey V</creatorcontrib><creatorcontrib>Shevelyova, Marina P</creatorcontrib><creatorcontrib>Tikhomirova, Natalia K</creatorcontrib><creatorcontrib>Philippov, Pavel P</creatorcontrib><creatorcontrib>Vasil'ev, Vasiliy G</creatorcontrib><creatorcontrib>Sergeeva, Marina G</creatorcontrib><creatorcontrib>Permyakov, Sergei E</creatorcontrib><creatorcontrib>Iomdina, Elena N</creatorcontrib><creatorcontrib>Tsvetkov, Philipp O</creatorcontrib><creatorcontrib>Senin, Ivan I</creatorcontrib><creatorcontrib>Zernii, Evgeni Yu</creatorcontrib><title>Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Autoimmune uveitis is a relapsing blind-causing ocular condition with complex pathogenesis that is not completely understood. There is a high demand for accurate animal models of experimental autoimmune uveitis (EAU) suitable for elucidating the molecular mechanisms of the disease and testing new therapeutic approaches. Here, we demonstrated that photoreceptor Ca
/Zn
-sensor protein recoverin is a uveoretinal antigen in albino rabbits provoking typical autoimmune chorioretinitis 2-4 weeks after immunization. The pathologic process in recoverin-induced EAU shared features with human disease and included lymphocytic infiltration of the retina, Dalen-Fuchs nodules and foci of subtotal or total retinal atrophy, manifested as a decrease in amplitude of the a-wave of the electroretinogram. In some cases, changes in the retinal vascular pattern and subretinal hemorrhages were also observed. These signs were accompanied by a gradual accumulation of serum antibodies against recoverin. Biochemical examination of the aqueous humor (AH) revealed typical characteristics of inflammation and oxidative stress, including increased levels of TNF-α and IL-6 and decreased levels of IL-10, as well as decreased total antioxidant activity, superoxide dismutase and glutathione peroxidase activities, and increased zinc concentration. Consistently, metabolomic and targeted lipidomic analysis of AH showed high lactate and low ascorbic acid levels in early EAU; increased levels of key pro-inflammatory signaling lipids such as PGE2, TXB2, 11-HETE and Lyso-PAF; and reduced levels of the anti-inflammatory fatty acid DHA in advanced stages of the disease. Uveitic AH became enriched with recoverin, confirming disruption of the blood-ocular barrier and photoreceptor damage. Notably, the application of mitochondria-targeted antioxidant therapy impeded EAU progression by maintaining local antioxidant activity and suppressing TNF-α, IL-6 and PGE2 signaling. Overall, our results demonstrate that recoverin-induced EAU in rabbits represents an accurate model of human autoimmune posterior uveitis and suggest new directions for its therapy that can be trialed using the developed model.</description><subject>Albinism</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Autoimmune Diseases</subject><subject>Autoimmune Diseases - immunology</subject><subject>Autoimmune Diseases - metabolism</subject><subject>Autoimmune Diseases - pathology</subject><subject>B cells</subject><subject>Cytokines</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Edema</subject><subject>Fatty acids</subject><subject>Health aspects</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Lactates</subject><subject>Life Sciences</subject><subject>Lymphocytes</subject><subject>Organic compounds</subject><subject>Oxidative Stress</subject><subject>Photoreceptors</subject><subject>Prostaglandins E</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Retina</subject><subject>Retina - 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There is a high demand for accurate animal models of experimental autoimmune uveitis (EAU) suitable for elucidating the molecular mechanisms of the disease and testing new therapeutic approaches. Here, we demonstrated that photoreceptor Ca
/Zn
-sensor protein recoverin is a uveoretinal antigen in albino rabbits provoking typical autoimmune chorioretinitis 2-4 weeks after immunization. The pathologic process in recoverin-induced EAU shared features with human disease and included lymphocytic infiltration of the retina, Dalen-Fuchs nodules and foci of subtotal or total retinal atrophy, manifested as a decrease in amplitude of the a-wave of the electroretinogram. In some cases, changes in the retinal vascular pattern and subretinal hemorrhages were also observed. These signs were accompanied by a gradual accumulation of serum antibodies against recoverin. Biochemical examination of the aqueous humor (AH) revealed typical characteristics of inflammation and oxidative stress, including increased levels of TNF-α and IL-6 and decreased levels of IL-10, as well as decreased total antioxidant activity, superoxide dismutase and glutathione peroxidase activities, and increased zinc concentration. Consistently, metabolomic and targeted lipidomic analysis of AH showed high lactate and low ascorbic acid levels in early EAU; increased levels of key pro-inflammatory signaling lipids such as PGE2, TXB2, 11-HETE and Lyso-PAF; and reduced levels of the anti-inflammatory fatty acid DHA in advanced stages of the disease. Uveitic AH became enriched with recoverin, confirming disruption of the blood-ocular barrier and photoreceptor damage. Notably, the application of mitochondria-targeted antioxidant therapy impeded EAU progression by maintaining local antioxidant activity and suppressing TNF-α, IL-6 and PGE2 signaling. Overall, our results demonstrate that recoverin-induced EAU in rabbits represents an accurate model of human autoimmune posterior uveitis and suggest new directions for its therapy that can be trialed using the developed model.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>39684616</pmid><doi>10.3390/ijms252312910</doi><orcidid>https://orcid.org/0000-0001-8143-3606</orcidid><orcidid>https://orcid.org/0000-0002-7625-9110</orcidid><orcidid>https://orcid.org/0000-0003-4086-3137</orcidid><orcidid>https://orcid.org/0000-0003-0137-8585</orcidid><orcidid>https://orcid.org/0009-0004-7638-5143</orcidid><orcidid>https://orcid.org/0000-0002-8622-8836</orcidid><orcidid>https://orcid.org/0000-0001-9664-9506</orcidid><orcidid>https://orcid.org/0000-0002-3013-7863</orcidid><orcidid>https://orcid.org/0000-0002-7764-693X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2024-12, Vol.25 (23), p.12910 |
| issn | 1422-0067 1661-6596 1422-0067 1661-6596 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_04893439v1 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Albinism Amino acids Analysis Animals Antibodies Antigens Autoimmune Diseases Autoimmune Diseases - immunology Autoimmune Diseases - metabolism Autoimmune Diseases - pathology B cells Cytokines Disease Disease Models, Animal Edema Fatty acids Health aspects Inflammation Inflammation - metabolism Lactates Life Sciences Lymphocytes Organic compounds Oxidative Stress Photoreceptors Prostaglandins E Proteins Rabbits Retina Retina - metabolism Retina - pathology Retinal detachment Thymus gland Uveitis Uveitis - drug therapy Uveitis - immunology Uveitis - metabolism Uveitis - pathology Viral antibodies |
| title | Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T07%3A07%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20Oxidative%20Stress%20and%20Inflammation%20in%20the%20Eye:%20Insights%20from%20a%20New%20Model%20of%20Experimental%20Autoimmune%20Uveitis&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Chistyakov,%20Dmitry%20V&rft.date=2024-12-01&rft.volume=25&rft.issue=23&rft.spage=12910&rft.pages=12910-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms252312910&rft_dat=%3Cgale_hal_p%3EA819951671%3C/gale_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3144192323&rft_id=info:pmid/39684616&rft_galeid=A819951671&rfr_iscdi=true |