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Immune Pathogenesis and Regulation of Ocular Inflammation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 41579

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Special Issue Editors

Prof. Dr. Junko Hori

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Guest Editor

Department of Ophthalmology, Nippon Medical School, Tama-Nagayama Hospital, Tokyo 2068512, Japan
Interests: immune privilege; ocular immunology; immune checkpoints; ocular inflammatory disease; corneal transplantation

Assoc. Prof. Dr. Hiroshi Keino

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Guest Editor

Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan
Interests: ocular inflammation; uveitis; ocular immune privilege; regulatory T cells; autoimmunity; immune tolerance

Assoc. Prof. Dr. Takefumi Yamaguchi

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Guest Editor

Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
Interests: Corneal transplantation; blood aqueous barrier; aqueous humor; immune privilege; visual optics; cornea

Special Issue Information

Dear Colleagues,

Immune responses and inflammation play a key role in a diverse range of eye diseases. In recent years, our understanding of ocular immune responses has widely spread in ocular surface inflammation, uveitis, and transplantation rejection, ocular tumor, age-related macular degeneration, diabetic retinopathy, glaucoma, and optic neuropathy. It is becoming increasingly clear that multiple seemingly unrelated diseases involve immune responses with common themes in their pathogenesis. Overlapping mechanisms raise the possibility that research on disparate topics will relate and opens the possibility for development of management strategies effective against a multitude of conditions.

This Special Issue will comprise a selection of research papers and reviews that will provide current knowledge of molecule- and cell-mediated immunity including functions of various types of immune cells and ocular tissue cells in the ocular inflammation. The mechanisms of immune pathogenesis and self-regulation of ocular inflammation will be highlighted. This issue will provide insight on future research and therapeutic approaches.

Prof. Dr. Junko Hori
Dr. Hiroshi Keino
Dr. Takefumi Yamaguchi
Guest Editors

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Keywords

ocular surface inflammation
corneal inflammation
corneal transplantation immunity
uveitis
scleritis
retinal vasculitis
ocular tumor
age-related macular degeneration
diabetic retinopathy
auto-immune retinopathy
glaucoma
optic neuropathy
ocular inflammation
ocular immunology
anterior chamber-associated immune deviation
immune privilege
iPS-derived ocular cell transplantation

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Published Papers (12 papers)

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Research

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14 pages, 4158 KiB

Open AccessArticle

Circulating Vitreous microRNA as Possible Biomarker in High Myopic Eyes with Macular Hole

by Yoshimasa Ando, Hiroshi Keino, Makoto Inoue, Kazunari Hirota, Hiroyuki Takahashi, Kimihiko Sano, Takashi Koto, Tomohito Sato, Masaru Takeuchi and Akito Hirakata

Int. J. Mol. Sci. 2022, 23(7), 3647; https://doi.org/10.3390/ijms23073647 - 26 Mar 2022

Cited by 9 | Viewed by 2944

Abstract

High myopia is a major cause of irreversible visual impairment globally. In the present study, we investigated the microRNA (miRNA) profile in the vitreous of macular hole (MH) and high myopic MH. We performed miRNA analysis using TaqMan^® Low Density Arrays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate the circulating vitreous miRNA profile from patients with MH (axial length < 26.5 mm, n = 11) and high myopic MH (axial length ≥ 26.5 mm, n = 11) who underwent pars plana vitrectomy. The vitreous inflammatory cytokine signature was examined in high myopic MH eyes using a multiplex assay. A miRNA-Array analysis revealed that let-7c was significantly up-regulated and miR-200a was significantly down-regulated in high myopic MH eyes compared to those in MH eyes. The bioinformatics analysis for up-regulated miRNA targeted gene identified 23 pathways including mitogen-activated protein kinase (MAPK) and several inflammatory signaling pathways, whereas the bioinformatics analysis for down-regulated miRNA targeted genes showed 32 enriched pathways including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). The levels of inflammatory cytokines including IP-10, IFN-γ, and MCP-1 were significantly higher in the vitreous of high myopic MH eyes. These results suggest that specific miRNAs expressed in the vitreous may be associated with the pathological condition of high myopic MH and the above mentioned miRNAs may contribute to the development of inflammatory status in the vitreous of high myopic eyes. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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17 pages, 10173 KiB

Open AccessArticle

Immunopathological Analysis of a Mouse Model of Arthritis-Associated Scleritis and Implications for Molecular Targeted Therapy for Severe Scleritis

by Yusuke Nishio, Hiroko Taniguchi, Ayaka Takeda and Junko Hori

Int. J. Mol. Sci. 2022, 23(1), 341; https://doi.org/10.3390/ijms23010341 - 29 Dec 2021

Cited by 8 | Viewed by 2241

Abstract

Scleritis involves inflammation of the sclera, which constitutes 75% of the wall of the eye. This pathology is often seen as an ocular lesion associated with systemic inflammatory diseases. Severe types of scleritis such as posterior scleritis require urgent immunosuppressive treatments, including molecularly targeted therapies to avoid permanent visual impairment. Which molecules should be selected as targets has remained unclear. To clarify the pathogenesis of scleritis and propose appropriate target molecules for therapy, we have established novel animal model of scleritis by modifying the Collagen-II Induced Arthritis (CIA) model. Immunization twice with collagen II emulsified with complete Freund’s adjuvant (CFA) caused arthritis and scleritis. The clinical appearance resembled human diffuse scleritis. Histopathological analysis suggested that macrophages, plasma cells, deposition of immune complexes, and growth of blood and lymphatic vessels are involved in the pathogenesis of CIA-associated scleritis. In addition, we analysed the background diseases of posterior scleritis and responses to molecularly targeted therapies as a case series study. We inferred from both the animal model and case series study that targets should not be T cells, but factors inhibiting macrophage activity such as tumor necrosis factor (TNF) and interleukin (IL)-6, and molecules suppressing antibody-producing cells such as CD20 on B cells should be targeted by molecularly targeted therapies. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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12 pages, 911 KiB

Open AccessArticle

Elevated Cytokine Levels in Aqueous Humor Are Associated with Peripheral Anterior Synechiae after Penetrating Keratoplasty

by Yuki Kusano, Takefumi Yamaguchi, Sota Nishisako, Takehiro Matsumura, Masaki Fukui, Kazunari Higa, Toshihiro Inoue and Jun Shimazaki

Int. J. Mol. Sci. 2021, 22(22), 12268; https://doi.org/10.3390/ijms222212268 - 12 Nov 2021

Cited by 4 | Viewed by 2427

Abstract

Peripheral anterior synechiae (PAS) after corneal transplantation leads to refractory glaucoma and permanent loss of vision. However, the exact mechanism remains elusive. This study aimed to evaluate the association between cytokine levels in the aqueous humor (AqH) and the progression of PAS after penetrating keratoplasty (PKP). We measured 20 cytokine levels in AqH and assessed the correlation with PAS progression after PKP in 85 consecutive patients who underwent PKP. We also evaluated age-dependent alterations in PAS and cytokine levels in DBA2J mice. PAS developed in 38 (44.7%) of 85 eyes after PKP. The incidence of intraocular pressure increase after PKP was significantly greater in eyes with PAS (26.3%) than in those without PAS (2%, p = 0.0009). The PAS area at 12 months after PKP was significantly positively correlated with the preoperative levels of interleukin (IL)-6, interferon (IFN)-γ and monocyte chemotactic protein (MCP)-1 (p ≤ 0.049). In the DBA2J mice, an experimental glaucoma model that developed PAS at 50 weeks, the AqH levels of IL-2, IL-6, IL-10, IFN-γ, tumor necrosis factor-α, MCP-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased at 50 weeks compared to 8 weeks (p ≤ 0.021). In conclusion, inflammatory alterations in the AqH microenvironment, such as high preoperative specific cytokine levels, can lead to PAS formation and glaucoma. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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13 pages, 2768 KiB

Open AccessArticle

Therapeutic Effect of α-MSH in Primary Cultured Orbital Fibroblasts Obtained from Patients with Thyroid Eye Disease

by Pei-Wen Cheng, Pei-Jhen Tsai, Ming-Hong Tai and Youn-Shen Bee

Int. J. Mol. Sci. 2021, 22(20), 11225; https://doi.org/10.3390/ijms222011225 - 18 Oct 2021

Cited by 2 | Viewed by 3041

Abstract

Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it’s toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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15 pages, 1844 KiB

Open AccessArticle

Adjunctive Thymosin Beta-4 Treatment Influences MΦ Effector Cell Function to Improve Disease Outcome in Pseudomonas aeruginosa-Induced Keratitis

by Yuxin Wang, Thomas W. Carion, Abdul Shukkur Ebrahim, Gabriel Sosne and Elizabeth A. Berger

Int. J. Mol. Sci. 2021, 22(20), 11016; https://doi.org/10.3390/ijms222011016 - 13 Oct 2021

Cited by 6 | Viewed by 2489

Abstract

Our previous work has shown that topical thymosin beta 4 (Tβ4) as an adjunct to ciprofloxacin treatment reduces inflammatory mediators and inflammatory cell infiltrates (neutrophils/PMN and macrophages/MΦ) while enhancing bacterial killing and wound healing pathway activation in an experimental model of P. aeruginosa-induced keratitis. This study aimed to mechanistically examine how Tβ4 influences MΦ function in particular, leading to reduced inflammation and enhanced host defense following P. aeruginosa-induced infection of the cornea. Flow cytometry was conducted to profile the phenotype of infiltrating MΦ after infection, while generation of reactive nitrogen species and markers of efferocytosis were detected to assess functional activity. In vitro studies were performed utilizing RAW 264.7 cells to verify and extend the in vivo findings. Tβ4 treatment decreases MΦ infiltration and regulates the activation state in response to infected corneas. MΦ functional data demonstrated that the adjunctive Tβ4 treatment group significantly downregulated reactive nitrogen species (RNS) production and efferocytotic activity. In addition, the in vitro studies showed that both Tβ4 alone and adjunctive Tβ4 treatment influenced MΦ cellular function following LPS stimulation. Collectively, these data provide further evidence that adjunctive Tβ4 + ciprofloxacin treatment offers a more efficacious option for treating bacterial keratitis. Not only does the adjunctive therapy address both the infectious pathogen and corneal wound healing response, but it also influences MΦ infiltration, activation, and function, as revealed by the current study. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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14 pages, 2234 KiB

Open AccessArticle

Anandamide Concentration-Dependently Modulates Toll-Like Receptor 3 Agonism or UVB-Induced Inflammatory Response of Human Corneal Epithelial Cells

by Ágnes Angyal, Zsófia Pénzes, Shahrzad Alimohammadi, Dorottya Horváth, Lili Takács, György Vereb, Barbara Zsebik, Tamás Bíró, Kinga Fanni Tóth, Erika Lisztes, Balázs István Tóth, Attila Oláh and Attila Gábor Szöllősi

Int. J. Mol. Sci. 2021, 22(15), 7776; https://doi.org/10.3390/ijms22157776 - 21 Jul 2021

Cited by 5 | Viewed by 3020

Abstract

Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids. p(I:C) and UVB irradiation was effective in promoting the transcription and secretion of inflammatory cytokines. Surprisingly, when applied alone in 100 nM and 10 μM, AEA also resulted in increased pro-inflammatory cytokine production. Importantly, AEA further increased levels of these cytokines in the UVB model, whereas its lower concentration partially prevented the transcriptional effect of p(I:C), while not decreasing the p(I:C)-induced cytokine release. HCECs express the enzymatic machinery required to produce endocannabinoids both in vitro and in situ. Moreover, our data show that, despite earlier reports about the anti-inflammatory potential of AEA in murine cornea, its effects on the immune phenotype of human corneal epithelium may be more complex and context dependent. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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Review

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17 pages, 1315 KiB

Open AccessReview

Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies

by Samanta Taurone, Chiara De Ponte, Dante Rotili, Elena De Santis, Antonello Mai, Francesco Fiorentino, Susanna Scarpa, Marco Artico and Alessandra Micera

Int. J. Mol. Sci. 2022, 23(7), 4048; https://doi.org/10.3390/ijms23074048 - 6 Apr 2022

Cited by 13 | Viewed by 3165

Abstract

Diabetic retinopathy (DR) is undoubtedly one of the most prominent causes of blindness worldwide. This pathology is the most frequent microvascular complication arising from diabetes, and its incidence is increasing at a constant pace. To date, the insurgence of DR is thought to be the consequence of the intricate complex of relations connecting inflammation, the generation of free oxygen species, and the consequent oxidative stress determined by protracted hyperglycemia. The sirtuin (SIRT) family comprises 7 histone and non-histone protein deacetylases and mono (ADP-ribosyl) transferases regulating different processes, including metabolism, senescence, DNA maintenance, and cell cycle regulation. These enzymes are involved in the development of various diseases such as neurodegeneration, cardiovascular pathologies, metabolic disorders, and cancer. SIRT1, 3, 5, and 6 are key enzymes in DR since they modulate glucose metabolism, insulin sensitivity, and inflammation. Currently, indirect and direct activators of SIRTs (such as antagomir, glycyrrhizin, and resveratrol) are being developed to modulate the inflammation response arising during DR. In this review, we aim to illustrate the most important inflammatory and metabolic pathways connecting SIRT activity to DR, and to describe the most relevant SIRT activators that might be proposed as new therapeutics to treat DR. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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27 pages, 7568 KiB

Open AccessReview

An Experimental Model of Neuro–Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells

by Laura Frutos-Rincón, José Antonio Gómez-Sánchez, Almudena Íñigo-Portugués, M. Carmen Acosta and Juana Gallar

Int. J. Mol. Sci. 2022, 23(6), 2997; https://doi.org/10.3390/ijms23062997 - 10 Mar 2022

Cited by 9 | Viewed by 5548

Abstract

The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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10 pages, 788 KiB

Open AccessReview

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

by Yi-Hsing Chen, Sue Lightman, Malihe Eskandarpour and Virginia L. Calder

Int. J. Mol. Sci. 2022, 23(1), 503; https://doi.org/10.3390/ijms23010503 - 3 Jan 2022

Cited by 12 | Viewed by 3033

Abstract

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4⁺ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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22 pages, 2698 KiB

Open AccessReview

Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives

by Fabiana Mallone, Roberta Costi, Marco Marenco, Rocco Plateroti, Antonio Minni, Giuseppe Attanasio, Marco Artico and Alessandro Lambiase

Int. J. Mol. Sci. 2021, 22(21), 11748; https://doi.org/10.3390/ijms222111748 - 29 Oct 2021

Cited by 26 | Viewed by 4587

Abstract

Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFβ or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFβ-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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20 pages, 3455 KiB

Open AccessReview

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

by Hyung-Keun Lee, Sang-Mok Lee and Dong-Ihll Lee

Int. J. Mol. Sci. 2021, 22(21), 11628; https://doi.org/10.3390/ijms222111628 - 27 Oct 2021

Cited by 17 | Viewed by 3105

Abstract

The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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13 pages, 293 KiB

Open AccessReview

CD4⁺ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

by Yi-Hsing Chen, Sue Lightman and Virginia L. Calder

Int. J. Mol. Sci. 2021, 22(17), 9584; https://doi.org/10.3390/ijms22179584 - 3 Sep 2021

Cited by 27 | Viewed by 4166

Abstract

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4⁺ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4⁺FoxP3⁺CD25⁺ regulatory T cells (Tregs) were known to suppress function of effector CD4⁺ T cells and contribute to resolution of disease. It has been recently reported that some CD4⁺ T-cell subsets demonstrate shared phenotypes with another CD4⁺ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4⁺ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease. Full article

(This article belongs to the Special Issue Immune Pathogenesis and Regulation of Ocular Inflammation)

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