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Immune Homeostasis and Regulation at the Surface of the Eye

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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 November 2022) | Viewed by 11976

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Special Issue Editors

Dr. Sharmila Masli

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Guest Editor

Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA
Interests: ocular mucosal immunology; autoimmunity; Sjögren’s syndrome; conjunctiva; lacrimal gland inflammation

Dr. Daniel Saban

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Guest Editor

Departments of Ophthalmology and Immunology, Duke University School of Medicine, Durham, NC 27708, USA
Interests: ocular immunology; neuroimmunology; myeloid cell biology; macrophage ontogeny

Dr. Anthony St Leger

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Guest Editor

Department of Ophthalmology, The University of Pittsburgh, Pittsburgh, PA, USA
Interests: ocular microbiome and immunity; anti-viral immunity; neuroimmunology; ocular mucosal immunity; innate immunity

Special Issue Information

Dear Colleagues,

The ocular surface is persistently exposed to environmental factors and microbes. The physical and cellular components of the tissues of the eye and the adnexa co-ordinate the maintenance of normal eyesight through a homeostatic process. This includes the maintenance of physical and physiological barriers to protect ocular tissues from damage caused by external factors. Tightly regulated immune responses contribute to such a defense by helping to eliminate damaging factors and re-establishing homeostasis. This is achieved through several modulatory mechanisms that actively resolve inflammation and help restore any bystander tissue damage to restore normal function. A delicate balance between inflammation and resolution is critical for normal eyesight. Any persistent tissue damage resulting from unresolved inflammation compromises their normal function and culminates in chronic pathology. As our understanding of the ocular microbiome is evolving, it is becoming evident that complex cross-regulatory mechanisms between commensal microbes, resident local immune cells and structural cells of ocular tissues likely regulate ocular mucosal homeostasis.

In this Special Issue, we invite contributions that provide novel insights to further advance our understanding of the cellular and molecular mechanisms involved in the regulation of ocular mucosal homeostasis in health and their deregulation leading to chronic diseases, including new therapeutic or diagnostic approaches for restoring homeostasis.

Dr. Sharmila Masli
Dr. Daniel Saban
Dr. Anthony St Leger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ocular mucosal immunology
ocular mucosal homeostasis
ocular inflammation
ocular microbiome
conjunctiva
cornea
lacrimal gland

Published Papers (5 papers)

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Research

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19 pages, 6020 KiB

Open AccessArticle

Topographical Distribution and Phenotype of Resident Meibomian Gland Orifice Immune Cells (MOICs) in Mice and the Effects of Topical Benzalkonium Chloride (BAK)

by Ching Yi Wu, Mengliang Wu, Xin Huang, Ben J. Gu, Carole Maldonado-Codina, Philip B. Morgan, Laura E. Downie and Holly R. Chinnery

Int. J. Mol. Sci. 2022, 23(17), 9589; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179589 - 24 Aug 2022

Cited by 1 | Viewed by 1589

Abstract

Meibomian gland orifices (MGOs) are located along the eyelid margin and secrete meibum into the tear film. The profile of resident innate immune cells (ICs) at this site is not well understood. The distribution and phenotype of resident ICs around MGOs in mice was investigated and herein defined as MGO-associated immune cells (MOICs). The effect of topical 0.1% benzalkonium chloride (BAK) on MOICs was also assessed. Eyelids from healthy CD11c^eYFP and Cx3cr1^gfp/gfp mice aged three or seven months were compared. ICs were identified as CD11c⁺, Cx3cr1⁺, and MHC-II⁺ using four-colour immunostaining and confocal microscopy. MOIC density was variable but clustered around MGOs. There were more CD11c⁺ MOICs in three-month-old compared with seven-month-old mice (three-month-old: 893

\pm

449 cells/mm² vs. seven-month-old: 593

\pm

493 cells/mm², p = 0.004). Along the eyelid margin, there was a decreasing gradient of CD11c⁺ MOIC density in three-month-old mice (nasal: 1003

\pm

369 cells/mm², vs. central: 946

\pm

574 cells/mm², vs. temporal: 731

\pm

353 cells/mm², p = 0.044). Cx3cr1-deficient mice had two-fold fewer MHC-II⁺ MOICs, suggesting a role for Cx3cr1 receptor signaling in meibomian gland surveillance. CD11c⁺ MOIC density was lower in BAK-exposed eyes compared to saline-treated controls, suggesting a change in homeostasis. This study provides novel insight into resident ICs located at MGOs, and their contribution to MG homeostasis. Full article

(This article belongs to the Special Issue Immune Homeostasis and Regulation at the Surface of the Eye)

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20 pages, 4544 KiB

Open AccessArticle

Signaling Pathways Used by the Specialized Pro-Resolving Mediator Maresin 2 Regulate Goblet Cell Function: Comparison with Maresin 1

by Markus V. Olsen, Anne V. Lyngstadaas, Jeffrey A. Bair, Robin R. Hodges, Tor P. Utheim, Charles N. Serhan and Darlene A. Dartt

Int. J. Mol. Sci. 2022, 23(11), 6233; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116233 - 02 Jun 2022

Cited by 4 | Viewed by 1934

Abstract

Specialized pro-resolving mediators (SPMs), including Maresins (MaR)-1 and 2, contribute to tear film homeostasis and resolve conjunctival inflammation. We investigated MaR2′s signaling pathways in goblet cells (GC) from rat conjunctiva. Agonist-induced [Ca²⁺]_i and high-molecular weight glycoconjugate secretion were measured. MaR2 increased [Ca²⁺]_i and stimulated secretion. MaR2 and MaR1 stimulate conjunctival goblet cell function, especially secretion, by activating different but overlapping GPCR and signaling pathways, and furthermore counter-regulate histamine stimulated increase in [Ca²⁺]_i. Thus, MaR2 and MaR1 play a role in maintaining the ocular surface and tear film homeostasis in health and disease. As MaR2 and MaR1 modulate conjunctival goblet cell function, they each may have potential as novel, but differing, options for the treatment of ocular surface inflammatory diseases including allergic conjunctivitis and dry eye disease. We conclude that in conjunctival GC MaR2 and MaR1, both increase the [Ca²⁺]_i and stimulate secretion to maintain homeostasis by using one set of different, but overlapping, signaling pathways to increase [Ca²⁺]_i and another set to stimulate secretion. MaR2 also resolves ocular allergy. Full article

(This article belongs to the Special Issue Immune Homeostasis and Regulation at the Surface of the Eye)

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Figure 1

12 pages, 2581 KiB

Open AccessArticle

Characterization of Recruited Mononuclear Phagocytes following Corneal Chemical Injury

by Ricardo Lamy, Marie Wolf, Claudia Bispo, Selene M. Clay, Siyu Zheng, Finn Wolfreys, Peipei Pan and Matilda F. Chan

Int. J. Mol. Sci. 2022, 23(5), 2574; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052574 - 25 Feb 2022

Cited by 4 | Viewed by 1569

Abstract

Mononuclear phagocytes (MP) have central importance in innate immunity, inflammation, and fibrosis. Recruited MPs, such as macrophages, are plastic cells and can switch from an inflammatory to a restorative phenotype during the healing process. However, the role of the MPs in corneal wound healing is not completely understood. The purpose of this study is to characterize the kinetics of recruited MPs and evaluate the role of macrophage metalloelastase (MMP12) in the healing process, using an in vivo corneal chemical injury model. Unwounded and wounded corneas of wild-type (WT) and Mmp12^−/− mice were collected at 1, 3, and 6 days after chemical injury and processed for flow cytometry analysis. Corneal MP phenotype significantly changed over time with recruited Ly6C^high (proinflammatory) cells being most abundant at 1 day post-injury. Ly6C^int cells were highly expressed at 3 days post-injury and Ly6C^neg (patrolling) cells became the predominant cell type at 6 days post-injury. CD11c⁺ dendritic cells were abundant in corneas from Mmp12^−/− mice at 6 days post-injury. These findings show the temporal phenotypic plasticity of recruited MPs and provide valuable insight into the role of the MPs in the corneal repair response, which may help guide the future development of MP-targeted therapies. Full article

(This article belongs to the Special Issue Immune Homeostasis and Regulation at the Surface of the Eye)

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19 pages, 33838 KiB

Open AccessArticle

Resolvin D2 and Resolvin D1 Differentially Activate Protein Kinases to Counter-Regulate Histamine-Induced [Ca²⁺]_i Increase and Mucin Secretion in Conjunctival Goblet Cells

by Menglu Yang, Nora Botten, Robin Hodges, Jeffrey Bair, Tor P. Utheim, Charles N. Serhan and Darlene A. Dartt

Int. J. Mol. Sci. 2022, 23(1), 141; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010141 - 23 Dec 2021

Cited by 3 | Viewed by 2738

Abstract

Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca²⁺] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca²⁺]_i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca²⁺]_i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated. Full article

(This article belongs to the Special Issue Immune Homeostasis and Regulation at the Surface of the Eye)

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Review

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23 pages, 15193 KiB

Open AccessReview

New Therapeutic Approaches for Conjunctival Melanoma—What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells

by Jennifer Peil, Felix Bock, Friedemann Kiefer, Rebecca Schmidt, Ludwig M. Heindl, Claus Cursiefen and Simona L. Schlereth

Int. J. Mol. Sci. 2022, 23(3), 1478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031478 - 27 Jan 2022

Cited by 3 | Viewed by 3387

Abstract

Conjunctival melanoma (CM) accounts for 5% of all ocular melanomas and arises from malignantly transformed melanocytes in the conjunctival epithelium. Current therapies using surgical excision in combination with chemo- or cryotherapy still have high rates for recurrences and metastatic disease. Lately, novel signal transduction-targeted and immune checkpoint inhibitors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) receptor inhibitors, BRAF- or MEK-inhibitors for systemic treatment of melanoma have improved the outcome even for unresectable cutaneous melanoma, improving patient survival dramatically. The use of these therapies is now also recommended for CM; however, the immunological background of CM is barely known, underlining the need for research to better understand the immunological basics when treating CM patients with immunomodulatory therapies. Immune checkpoint inhibitors activate tumor defense by interrupting inhibitory interactions between tumor cells and T lymphocytes at the so-called checkpoints. The tumor cells exploit these inhibitory targets on T-cells that are usually used by dendritic cells (DCs). DCs are antigen-presenting cells at the forefront of immune response induction. They contribute to immune tolerance and immune defense but in the case of tumor development, immune tolerance is often prevalent. Enhancing the immune response via DCs, interfering with the lymphatic pathways during immune cell migration and tumor development and specifically targeting tumor cells is a major therapeutic opportunity for many tumor entities including CM. This review summarizes the current knowledge on the function of lymphatic vessels in tumor growth and immune cell transport and continues to compare DC subsets in CM with related melanomas, such as cutaneous melanoma and mucosal melanoma. Full article

(This article belongs to the Special Issue Immune Homeostasis and Regulation at the Surface of the Eye)

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