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Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies
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Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 October 2024) | Viewed by 14611

Special Issue Editors

Prof. Dr. Valery Shestopalov

E-Mail Website
Guest Editor
Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
Interests: neuroinflammation, responses in neurodegenerative disorders of the retina and optic nerve; accelerated ageing and cellular senescence in mechanically stressed cells; purinergic signaling and channelopathies in retinal neurobiology and vision disorders; translational studies on biomarkers in neurological disorders; therapeutic modulation of disease-causative pathways, new therapeutic targets and disease biomarkers in glaucoma research; animal models of neurodegenerative disorders; bioinformatics and pathway analysis of OMICS data; human microbiome in ocular health and disease; lens development and cataract formation
Prof. Dr. Claire H. Mitchell

E-Mail Website
Guest Editor
Department of Basic & Translational Sciences, University of Pennsylvania, Philadelphia, PA, USA
Interests: neurodegeneration; lysosomes; purinergic signaling; aging cell; neuroinflammation; microglia; retina
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Rob Nickells

E-Mail Website
Guest Editor
Ophthalmology and Visual Sciences, University of Wisconsin - Madison, Madison, WI, USA
Interests: glaucoma; retinal cell death; ganglion cell loss

Special Issue Information

Dear Colleagues,

Eye diseases affecting the retina and optic nerve are cumulatively responsible for nearly 20% of the global burden of blindness, with three major ones being age-related macular degeneration, diabetic retinopathy and glaucoma. Degenerations of photoreceptors and retinal pigment epithelium (RPE) in age-related macular degeneration (AMD), diabetic retinopathy and retinitis pigmentosa cause blindness through the dysfunction of the outer retina causing loss of photoreceptors. Progressive optic nerve degeneration in glaucomatous, ischemic and traumatic optic neuropathies, as well as multiple sclerosis and optic nerve injuries result in visual field loss and irreversible blindness due to retrograde death of retinal ganglion cells. Diverse mechanisms, molecular mechanisms and cell interactions are implicated in each of these pathologies; however, major risk factors including genetics, impaired regulation of blood circulation, mitochondrial dysfunction, chronic neuroinflammation, stress, etc., are commonly present and significantly affecting the outcome. The majority of people with vision impairment and blindness are over the age of 50 years, strongly indicating the involvement of cellular senescence, oxidative stress and immune system dysregulation. An in-depth understanding and prioritization of the mechanisms commonly guides researchers towards innovative treatment paradigms of vision preservation through neuroprotection. This Special Issue focuses on the key pathological mechanisms, both disease-unique and common ones, underlying diverse optic nerve and retinal degenerations, as well as the emerging therapeutic strategies targeting them.

Prof. Dr. Valery Shestopalov
Prof. Dr. Claire H. Mitchell
Prof. Dr. Rob Nickells
Guest Editors

Manuscript Submission Information

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Keywords

  • retina
  • optic nerve
  • neurodegeneration
  • disease mechanisms
  • neuroprotection
  • inflammation
  • senescence

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Published Papers (7 papers)

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15 pages, 1431 KiB  
Article
CD3+CD4-CD8- Double-Negative Lymphocytes Are Increased in the Aqueous Humor of Patients with Retinitis Pigmentosa: Their Possible Role in Mediating Inflammation
by Daniela Bacherini, Laura Maggi, Francesco Faraldi, Andrea Sodi, Lorenzo Vannozzi, Alessio Mazzoni, Manuela Capone, Gianni Virgili, Giulio Vicini, Benedetto Falsini, Lorenzo Cosmi, Pasquale Viggiano, Stanislao Rizzo, Francesco Annunziato, Fabrizio Giansanti and Francesco Liotta
Int. J. Mol. Sci. 2024, 25(23), 13163; https://doi.org/10.3390/ijms252313163 - 7 Dec 2024
Viewed by 1042
Abstract
Recently, evidence has supported a significant role for immune and oxidative-mediated damage underlying the pathogenesis of different types of retinal diseases, including retinitis pigmentosa (RP). Our study aimed to evaluate the presence of immune cells and mediators in patients with RP using flow [...] Read more.
Recently, evidence has supported a significant role for immune and oxidative-mediated damage underlying the pathogenesis of different types of retinal diseases, including retinitis pigmentosa (RP). Our study aimed to evaluate the presence of immune cells and mediators in patients with RP using flow cytometric analysis of peripheral blood (PB) and aqueous humor (AH) samples. We recruited 12 patients with RP and nine controls undergoing cataract surgery. Flow cytometric analysis of PB and AH samples provided a membrane staining that targeted surface molecules (CD14, CD16, CD19, CD3, CD4, CD8, and CD161) identifying monocytes, natural killer (NK) cells, B cells, T cells, and T subpopulations, respectively. Moreover, lymphocytes were polyclonally stimulated to evaluate cytokine (CK) production at single-cell level. The circulating immune cell distribution was comparable between patients with RP and controls. Conversely, in the AH of controls we could detect no cells, while in the RP AH samples we found infiltrating leukocytes, consisting of T (CD3+), B (CD19+), NK (CD16+CD3-) cells, and monocytes (CD14+). In patients with RP, the frequency of most infiltrating immune cell populations was similar between the AH and PB. However, among T cell subpopulations, the frequency of CD3+CD4+ T cells was significantly lower in the RP AH compared to RP PB, whereas CD3+CD4-CD8- double-negative (DN) T cells were significantly higher in the RP AH compared to RP PB. Cytokine production analysis revealed a trend toward an increased frequency of CD3+CD8-CD161+IFN-ɣ-producing cells and a decreased frequency of CD3+CD8+IL-4-producing cells in the RP AH compared to RP PB. The detection of immune cells, particularly DN T cells, and a Th1-skewed phenotype in RP AH suggests immune-mediated and inflammatory mechanisms in the disease. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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20 pages, 9874 KiB  
Article
Targeting Oxidative Stress and Inflammation in the Eye: Insights from a New Model of Experimental Autoimmune Uveitis
by Dmitry V. Chistyakov, 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, Pavel P. Philippov, Vasiliy G. Vasil’ev, Marina G. Sergeeva, Sergei E. Permyakov, Elena N. Iomdina, Philipp O. Tsvetkov, Ivan I. Senin and Evgeni Yu. Zernii
Int. J. Mol. Sci. 2024, 25(23), 12910; https://doi.org/10.3390/ijms252312910 - 30 Nov 2024
Cited by 1 | Viewed by 1332
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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15 pages, 2691 KiB  
Article
Contralateral Astrocyte Response to Acute Optic Nerve Damage Is Mitigated by PANX1 Channel Activity
by Jasmine A. Wurl, Caitlin E. Mac Nair, Joel A. Dietz, Valery I. Shestopalov and Robert W. Nickells
Int. J. Mol. Sci. 2023, 24(21), 15641; https://doi.org/10.3390/ijms242115641 - 27 Oct 2023
Cited by 4 | Viewed by 1413
Abstract
Glial reactivity is considered a hallmark of damage-induced innate immune responses in the central nervous system. In the visual system, unilateral optic nerve damage elicits dramatic glial reactivity in the retina directly affected by the lesion and a similar, albeit more modest, effect [...] Read more.
Glial reactivity is considered a hallmark of damage-induced innate immune responses in the central nervous system. In the visual system, unilateral optic nerve damage elicits dramatic glial reactivity in the retina directly affected by the lesion and a similar, albeit more modest, effect in the contralateral eye. Evaluation of astrocyte changes in a mouse model of optic nerve crush indicates that astrocyte reactivity, as a function of retinal coverage and cellular hypertrophy, occurs within both the experimental and contralateral retinas, although the hypertrophic response of the astrocytes in the contralateral eyes is delayed for at least 24 h. Evaluation of astrocytic reactivity as a function of Gfap expression indicates a similar, muted but significant, response in contralateral eyes. This constrained glial response is completely negated by conditional knock out of Panx1 in both astrocytes and Müller cells. Further studies are required to identify if this is an autocrine or a paracrine suppression of astroglial reactivity. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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15 pages, 5755 KiB  
Article
Various Forms of Programmed Cell Death Are Concurrently Activated in the Population of Retinal Ganglion Cells after Ischemia and Reperfusion
by Galina Dvoriantchikova, Emily Adis, Karin Lypka and Dmitry Ivanov
Int. J. Mol. Sci. 2023, 24(12), 9892; https://doi.org/10.3390/ijms24129892 - 8 Jun 2023
Cited by 9 | Viewed by 2280
Abstract
Retinal ischemia–reperfusion (IR)—which ultimately results in retinal ganglion cell (RGC) death—is a common cause of visual impairment and blindness worldwide. IR results in various types of programmed cell death (PCD), which are of particular importance since they can be prevented by inhibiting the [...] Read more.
Retinal ischemia–reperfusion (IR)—which ultimately results in retinal ganglion cell (RGC) death—is a common cause of visual impairment and blindness worldwide. IR results in various types of programmed cell death (PCD), which are of particular importance since they can be prevented by inhibiting the activity of their corresponding signaling cascades. To study the PCD pathways in ischemic RGCs, we used a mouse model of retinal IR and a variety of approaches including RNA-seq analysis, knockout animals, and animals treated with an iron chelator. In our RNA-seq analysis, we utilized RGCs isolated from retinas 24 h after IR. In ischemic RGCs, we found increased expression of many genes that regulate apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos. Our data indicate that genetic ablation of death receptors protects RGCs from IR. We showed that the signaling cascades regulating ferrous iron (Fe2+) metabolism undergo significant changes in ischemic RGCs, leading to retinal damage after IR. This data suggests that the activation of death receptors and increased Fe2+ production in ischemic RGCs promote the simultaneous activation of apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos pathways. Thus, a therapy is needed that concurrently regulates the activity of the multiple PCD pathways to reduce RGC death after IR. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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16 pages, 971 KiB  
Review
Therapeutic Effects of Anti-Inflammatory and Anti-Oxidant Nutritional Supplementation in Retinal Ischemic Diseases
by Deokho Lee, Zhongjie Fu, Ann Hellstrom and Lois E. H. Smith
Int. J. Mol. Sci. 2024, 25(10), 5503; https://doi.org/10.3390/ijms25105503 - 18 May 2024
Cited by 3 | Viewed by 3346
Abstract
Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed [...] Read more.
Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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20 pages, 819 KiB  
Review
The Role of Complement Dysregulation in Glaucoma
by Cindy Hoppe and Meredith Gregory-Ksander
Int. J. Mol. Sci. 2024, 25(4), 2307; https://doi.org/10.3390/ijms25042307 - 15 Feb 2024
Cited by 6 | Viewed by 2504
Abstract
Glaucoma is a progressive neurodegenerative disease characterized by damage to the optic nerve that results in irreversible vision loss. While the exact pathology of glaucoma is not well understood, emerging evidence suggests that dysregulation of the complement system, a key component of innate [...] Read more.
Glaucoma is a progressive neurodegenerative disease characterized by damage to the optic nerve that results in irreversible vision loss. While the exact pathology of glaucoma is not well understood, emerging evidence suggests that dysregulation of the complement system, a key component of innate immunity, plays a crucial role. In glaucoma, dysregulation of the complement cascade and impaired regulation of complement factors contribute to chronic inflammation and neurodegeneration. Complement components such as C1Q, C3, and the membrane attack complex have been implicated in glaucomatous neuroinflammation and retinal ganglion cell death. This review will provide a summary of human and experimental studies that document the dysregulation of the complement system observed in glaucoma patients and animal models of glaucoma driving chronic inflammation and neurodegeneration. Understanding how complement-mediated damage contributes to glaucoma will provide opportunities for new therapies. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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15 pages, 1206 KiB  
Review
The Fibro-Inflammatory Response in the Glaucomatous Optic Nerve Head
by Emma K. Geiduschek and Colleen M. McDowell
Int. J. Mol. Sci. 2023, 24(17), 13240; https://doi.org/10.3390/ijms241713240 - 26 Aug 2023
Cited by 2 | Viewed by 1766
Abstract
Glaucoma is a progressive disease and the leading cause of irreversible blindness. The limited therapeutics available are only able to manage the common risk factor of glaucoma, elevated intraocular pressure (IOP), indicating a great need for understanding the cellular mechanisms behind optic nerve [...] Read more.
Glaucoma is a progressive disease and the leading cause of irreversible blindness. The limited therapeutics available are only able to manage the common risk factor of glaucoma, elevated intraocular pressure (IOP), indicating a great need for understanding the cellular mechanisms behind optic nerve head (ONH) damage during disease progression. Here we review the known inflammatory and fibrotic changes occurring in the ONH. In addition, we describe a novel mechanism of toll-like receptor 4 (TLR4) and transforming growth factor beta-2 (TGFβ2) signaling crosstalk in the cells of the ONH that contribute to glaucomatous damage. Understanding molecular signaling within and between the cells of the ONH can help identify new drug targets and therapeutics. Full article
(This article belongs to the Special Issue Emerging Roles of Inflammation in Retinal and Optic Nerve Pathologies)
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