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Article

Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis

by
Dmitry V. Chistyakov
1,2,
Veronika V. Tiulina
1,
Olga S. Gancharova
1,
Viktoriia E. Baksheeva
1,
Sergei V. Goriainov
2,
Natalia G. Shebardina
1,
Vasily A. Ivlev
2,
Sergey V. Komarov
3,
Marina P. Shevelyova
4,
Natalia K. Tikhomirova
1,
Pavel P. Philippov
1,
Vasiliy G. Vasil’ev
2,
Marina G. Sergeeva
1,
Sergei E. Permyakov
4,
Elena N. Iomdina
5,
Philipp O. Tsvetkov
6,*,
Ivan I. Senin
1 and
Evgeni Yu. Zernii
1,*
1
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
2
Pharmacy Resource Center, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
3
Skryabin Moscow State Academy of Veterinary Medicine and Biotechnology, 109472 Moscow, Russia
4
Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Russia
5
Helmholtz National Medical Research Center of Eye Diseases, 105062 Moscow, Russia
6
CNRS, UMR 7051, INP, Inst Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Aix Marseille Univ, 13005 Marseille, France
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(23), 12910; https://doi.org/10.3390/ijms252312910
Submission received: 15 October 2024 / Revised: 12 November 2024 / Accepted: 27 November 2024 / Published: 30 November 2024
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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Abstract

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 Ca2+/Zn2+-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.
Keywords: experimental autoimmune uveitis; recoverin; oxidative stress; aqueous humor lipidomics; oxylipins; polyunsaturated fatty acids; aqueous humor metabolomics; ascorbic acid; mitochondria-targeted antioxidant; SkQ1 experimental autoimmune uveitis; recoverin; oxidative stress; aqueous humor lipidomics; oxylipins; polyunsaturated fatty acids; aqueous humor metabolomics; ascorbic acid; mitochondria-targeted antioxidant; SkQ1

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MDPI and ACS Style

Chistyakov, D.V.; Tiulina, V.V.; Gancharova, O.S.; Baksheeva, V.E.; Goriainov, S.V.; Shebardina, N.G.; Ivlev, V.A.; Komarov, S.V.; Shevelyova, M.P.; Tikhomirova, N.K.; et al. Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis. Int. J. Mol. Sci. 2024, 25, 12910. https://doi.org/10.3390/ijms252312910

AMA Style

Chistyakov DV, Tiulina VV, Gancharova OS, Baksheeva VE, Goriainov SV, Shebardina NG, Ivlev VA, Komarov SV, Shevelyova MP, Tikhomirova NK, et al. Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis. International Journal of Molecular Sciences. 2024; 25(23):12910. https://doi.org/10.3390/ijms252312910

Chicago/Turabian Style

Chistyakov, Dmitry V., Veronika V. Tiulina, Olga S. Gancharova, Viktoriia E. Baksheeva, Sergei V. Goriainov, Natalia G. Shebardina, Vasily A. Ivlev, Sergey V. Komarov, Marina P. Shevelyova, Natalia K. Tikhomirova, and et al. 2024. "Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis" International Journal of Molecular Sciences 25, no. 23: 12910. https://doi.org/10.3390/ijms252312910

APA Style

Chistyakov, D. V., Tiulina, V. V., Gancharova, O. S., Baksheeva, V. E., Goriainov, S. V., Shebardina, N. G., Ivlev, V. A., Komarov, S. V., Shevelyova, M. P., Tikhomirova, N. K., Philippov, P. P., Vasil’ev, V. G., Sergeeva, M. G., Permyakov, S. E., Iomdina, E. N., Tsvetkov, P. O., Senin, I. I., & Zernii, E. Y. (2024). Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis. International Journal of Molecular Sciences, 25(23), 12910. https://doi.org/10.3390/ijms252312910

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