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      TGFβ1, MMPs and cytokines profiles in ocular surface: Possible tear biomarkers for pseudoexfoliation

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          Abstract

          Purpose

          Pseudoexfoliation (PXF) is a unique form of glaucoma characterized by accumulation of exfoliative material in the eyes. Changes in tear profile in disease stages may give us insights into molecular mechanisms involved in causing glaucoma in the eye.

          Methods

          All patients were categorized into three main categories; pseudoexfoliation (PXF), pseudoexfoliation glaucoma (PXG) and cataract, which served as control. Cytokines, transforming growth factor β1 (TGFβ1), matrix metalloproteases (MMPs) and fibronectin (FN1) were assessed with multiplex bead assay, enzyme-linked immunosorbent assay (ELISA), gelatin zymography, and immunohistochemistry (IHC) respectively in different ocular tissues such as tears, tenon’s capsule, aqueous humor (AH) and serum samples of patients with PXF stages.

          Results

          We found that TGFβ1, MMP-9 and FN1 protein expression were upregulated in tears, tenon’s capsule and AH samples in PXG compared to PXF, though the MMP-9 protein activity was downregulated in PXG compared with control or PXF. We have also found that in PXG tears sample the fold change of TGF-α (Transforming Growth Factor-α), MDC (Macrophage Derived Chemokine), IL-8 (Interleukin-8), VEGF (Vascular Endothelial Growth Factor) were significantly downregulated and the levels of GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), IP-10 (Interferon- γ produced protein-10) were significant upregulated. While in AH; IL-6 (Interleukin-6), IL-8, VEGF, IFN-a2 (Interferon- α2), GRO (Growth regulated alpha protein) levels were found lower and IL1a (Interleukin-1α) level was higher in PXG compared to PXF. And in serum; IFN-a2, Eotaxin, GM-CSF, Fractalkine, IL-10 (Interleukin-10), IL1Ra (Interleukin-1 receptor antagonist), IL-7 (Interleukin-7), IL-8, MIP1β (Macrophage Inflammatory Protein-1β), MCP-1 (Monocyte Chemoattractant Protein-1) levels were significantly upregulated and PDGF-AA (Platelet Derived Growth Factor-AA) level was downregulated in the patients with PXG compared to PXF.

          Conclusions

          Altered expression of these molecules in tears may therefore be used as a signal for onset of glaucoma or for identifying eyes at risk of developing glaucoma in PXF.

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          Most cited references40

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          Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions.

          Jane Sottile, Denise C. Hocking (2002)
          Remodeling of extracellular matrices occurs during development, wound healing, and in a variety of pathological processes including atherosclerosis, ischemic injury, and angiogenesis. Thus, identifying factors that control the balance between matrix deposition and degradation during tissue remodeling is essential for understanding mechanisms that regulate a variety of normal and pathological processes. Using fibronectin-null cells, we found that fibronectin polymerization into the extracellular matrix is required for the deposition of collagen-I and thrombospondin-1 and that the maintenance of extracellular matrix fibronectin fibrils requires the continual polymerization of a fibronectin matrix. Further, integrin ligation alone is not sufficient to maintain extracellular matrix fibronectin in the absence of fibronectin deposition. Our data also demonstrate that the retention of thrombospondin-1 and collagen I into fibrillar structures within the extracellular matrix depends on an intact fibronectin matrix. An intact fibronectin matrix is also critical for maintaining the composition of cell-matrix adhesion sites; in the absence of fibronectin and fibronectin polymerization, neither alpha5beta1 integrin nor tensin localize to fibrillar cell-matrix adhesion sites. These data indicate that fibronectin polymerization is a critical regulator of extracellular matrix organization and stability. The ability of fibronectin polymerization to act as a switch that controls the organization and composition of the extracellular matrix and cell-matrix adhesion sites provides cells with a means of precisely controlling cell-extracellular matrix signaling events that regulate many aspects of cell behavior including cell proliferation, migration, and differentiation.
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            TNF-alpha signaling in glaucomatous neurodegeneration.

            Gülgün Tezel (2008)
            Growing evidence supports the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of neurodegeneration in glaucoma. Glial production of TNF-alpha is increased, and its death receptor is upregulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. In addition to direct neurotoxicity, potential interplay of TNF-alpha signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to spreading neuronal damage by secondary degeneration. Opposing these cell death-promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-alpha as best exemplified by differential responses of RGCs and glia. This review focuses on the present evidence supporting the involvement of TNF-alpha signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.
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              Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences.

              Güler G Tezel (2006)
              Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. Although ROS are essential participants in cell signaling and regulation, when their cellular production overwhelms the intrinsic antioxidant capacity, damage to cellular macromolecules such as DNA, proteins, and lipids ensues. Such a state of "oxidative stress" is thought to contribute to the pathogenesis of a number of neurodegenerative diseases. Growing evidence supports the involvement of oxidative stress as a common component of glaucomatous neurodegeneration in different subcellular compartments of retinal ganglion cells (RGCs). Besides the evidence of direct cytotoxic consequences leading to RGC death, it also seems highly possible that ROS are involved in signaling RGC death by acting as a second messenger and/or modulating protein function by redox modifications of downstream effectors through enzymatic oxidation of specific amino acid residues. Different studies provide cumulating evidence, which supports the association of ROS with different aspects of the neurodegenerative process. Oxidative protein modifications during glaucomatous neurodegeneration increase neuronal susceptibility to damage and also lead to glial dysfunction. Oxidative stress-induced dysfunction of glial cells may contribute to spreading neuronal damage by secondary degeneration. Oxidative stress also promotes the accumulation of advanced glycation end products in glaucomatous tissues. In addition, oxidative stress takes part in the activation of immune response during glaucomatous neurodegeneration, as ROS stimulate the antigen presenting ability of glial cells and also function as co-stimulatory molecules during antigen presentation. By discussing current evidence, this review provides a broad perspective on cellular mechanisms and potential consequences of oxidative stress in glaucoma.
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                Author and article information

                Contributors
                Prity Sahay: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Shweta Reddy: Role: MethodologyRole: Writing – review & editing
                Birendra Kumar Prusty: Role: Data curationRole: Formal analysisRole: Software
                Rahul Modak: Role: SupervisionRole: Writing – review & editing
                Aparna Rao:
                ORCID: https://orcid.org/0000-0001-8120-8740
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Andrew W Taylor: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 29 April 2021
                Publication date Collection: 2021
                Volume: 16
                Issue: 4
                Electronic Location Identifier: e0249759
                Affiliations
                [1 ] Hyderabad Eye Research Foundation (HERF), L.V. Prasad Eye Institute, Patia, Bhubaneswar, Odisha, India
                [2 ] KIIT School of Biotechnology, Patia, Bhubaneswar, Odisha, India
                [3 ] Institute of Life Science, Bhubaneswar, Odisha, India
                Boston University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-8120-8740
                Article
                Publisher ID: PONE-D-21-01128
                DOI: 10.1371/journal.pone.0249759
                PMC ID: 8084233
                PubMed ID: 33914756
                SO-VID: feadc203-325f-44b3-877d-1908d4e82a77
                Copyright © © 2021 Sahay et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 12 January 2021
                Date accepted : 24 March 2021
                Page count
                Figures: 4, Tables: 2, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100009053, The Wellcome Trust DBT India Alliance;
                Award ID: IA/CPHI/15/1/502031
                Award Recipient :
                ORCID: https://orcid.org/0000-0001-8120-8740
                This work was supported by the DBT/Wellcome Trust India Alliance Fellowship IA/CPHI/15/1/502031 awarded to Aparna Rao and the glaucoma foundation grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Eye Diseases
                Subject: Glaucoma
                Subject: Medicine and Health Sciences
                Subject: Ophthalmology
                Subject: Eye Diseases
                Subject: Glaucoma
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Innate Immune System
                Subject: Cytokines
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Innate Immune System
                Subject: Cytokines
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Molecular Development
                Subject: Cytokines
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Signal transduction
                Subject: Cell signaling
                Subject: Signaling cascades
                Subject: TGF-beta signaling cascade
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Ocular Anatomy
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Ocular Anatomy
                Subject: Biology and Life Sciences
                Subject: Agriculture
                Subject: Animal Products
                Subject: Gelatin
                Subject: Research and Analysis Methods
                Subject: Specimen Preparation and Treatment
                Subject: Staining
                Subject: Immunostaining
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting information files.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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