Modulation of Integrin α4β1 (VLA-4) in Dry Eye Disease

Ecoiffier, Tatiana

doi:10.1001/archopht.126.12.1695

Cited by 55 publications

(39 citation statements)

References 28 publications

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“…21,25 These cytokines activate resident APCs and promote the corneal infiltration of additional CD11b þ cells. 26,27 Activated APCs subsequently stimulate an adaptive immune response, as evidenced by the proliferation of CD4 þ T cells in the draining lymphatics. 1,28 Furthermore, APCs prime pathogenic ocular surface-specific CD4 þ T cells (e.g., T helper 17 cells), supporting the theory that DED has an autoimmune component.…”

Section: Discussionmentioning

confidence: 99%

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Lee¹,

Hattori²,

Park³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED).METHODS. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1b, IL-6, TNF, and CCL2), corneal infiltration of CD11b 3 Recent studies have demonstrated that corneal epithelial cells respond to hyperosmolar stress by producing proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs).4,5 Furthermore, hyperosmolar stress and proinflammatory cytokines such as interferon (IFN)-c promote epithelial cell apoptosis. [5][6][7][8] Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize highly conserved microbial structures and products.9,10 To date, 12 murine TLRs have been identified, and TLRs are expressed by a variety of cell types, including epithelial cells, dendritic cells, macrophages, and lymphocytes.10-13 TLR stimulation leads to the activation of nuclear factor-kappaB (NF-jB) that upregulates the production of proinflammatory cytokines and antimicrobial proteins.10,14 The NF-jB signaling pathway is important for the induction of innate and adaptive immune responses. 10,14 TLR4 recognizes the Gram-negative bacterial cell wall component lipopolysaccharide (LPS) in association with cofactors such as CD14, LPS-binding protein (LBP), and myeloid differentiation factor-2 (MD-2). 15,16 It has also been suggested that TLR4 is a receptor for endogenous ligands associated with noninfectious diseases such as myocardial ischemia-reperfusion injury and central nervous system autoimmune disease. 17,18 We hypothesized that DED-induced corneal inflammation and injury may lead to the production of endogenous TLR4 ligands that activate the immune system. Therefore, we investigated the corneal expression of TLR4 and sought to determine the expression pattern of TLR4 in DED. MATERIALS AND METHODS AnimalsSeven to 8-week-old female C57BL/6 mice (Charles River Laboratories, Wilmington, MA) were used for these experiments. The experimental protocol was approved by the Institutional Animal Care and Use Committee, and all animals were managed according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Dry Eye ModelDED was induced by placing mice in a controlled environment chamber (CEC) and administering scopolamine (Sigma-Aldrich, St. Louis, MO) to maximize ocular surface dryness, as previously described. 19,20 Mice placed in the CEC were exposed to a relative humidity < 25%, temperature of 20 to 228C, and airflow of 15 L/min, 2...

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Section: Discussionmentioning

confidence: 99%

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Lee¹,

Hattori²,

Park³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Synthetic peptide antagonists of integrin αvβ3 inhibited retinal neovascularization in a murine model when administered as intraperitonal or periocular injections (Luna et al 1996), inhibition of αv integrins prevented basic fibroblast growth factor-induced neovascularization of cornea (Klotz et al 2000), and inhibition of α5β1 inhibited and regressed corneal neovascularization after alkali-burns (Muether et al 2007). Blockade of α4β1 decreased dry eye symptoms and inflammation significantly (Ecoiffier et al 2008). Furthermore, integrin signaling and integrin-linked kinase activity could affect the organization and contractility of actin cytoskeleton in trabecular meshwork cells (Faralli et al 2011), a factor known to modulate aqueous humor outflow.…”

Section: Established Functions Of Integrins In the Eye And Their Assomentioning

confidence: 99%

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Parapuram

Hodge

2014

J. Cell Commun. Signal.

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Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.Keywords Cornea . Keratocytes . Corneal stroma . Extracellular matrix . Integrins . KeratoconusThe simple cellular organization of the cornea is belied by its fascinating specialization for transparency. The cornea has three main tissue layers, the outer epithelium, the stroma in the middle and the inner endothelial layer. The stromal connective tissue, the layer mainly responsible for the corneal configuration, constituting nearly 80 % of the thickness of the cornea, is extremely resilient, capable of resisting intraocular pressure and protecting the posterior structures of the eye. The stromal tissue consists of lamellae of orthogonally arranged collagen fibrils surrounded by proteoglycans; in between the lamellae of collagen are found the keratocytes. The nearorderly arrangement of collagen lamellae, the narrow diameter of the collagen fibrils, regular interfibrillar space, associated proteoglycans and the expression of crystalline proteins in the keratocytes (Birk 2001;Kao and Liu 2002;Jester et al. 2007; Hassell and Birk 2010) are some of the main factors responsible for corneal transparency. Consequently, the factors affecting corneal transparency such as fibrotic changes due to disease or injury are problems primarily associated with the stroma. Thus it is important to achieve further understanding of the mechanisms by which the stroma acquires and maintains its structural integrity and its transparency.

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“…CD4 + T cells make a prominent contribution to chronic inflammation during the immunopathogenesis of dry eye, underscoring its basis as an autoimmune-based inflammatory disease. This notion is supported by several lines of evidence: 1) activated CD4 + T cells are localized within the ocular surface tissues of dry eye patients (5,6); 2) CD4 + T cells are sufficient to induce dry eye in mice (4); and 3) compounds that inhibit T cells (e.g., cyclosporine A) attenuate dry eye disease in both animals and humans (5,7). Dry eye disease, induced in a mouse model of autoimmune lacrimal keratoconjunctivitis (ALKC), is a valuable tool for defining the underlying mechanisms of CD4 + T cell-mediated disease (4).…”

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confidence: 92%

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

Schaumburg

Siemasko

Paiva

et al. 2011

The Journal of Immunology

134

126

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As specialized sentinels between the innate and adaptive immune response, APCs are essential for activation of Ag-specific lymphocytes, pathogen clearance, and generation of immunological memory. The process is tightly regulated; however, excessive or atypical stimuli may ignite activation of APCs in a way that allows self-Ag presentation to autoreactive T cells in the context of the necessary costimulatory signals, ultimately resulting in autoimmunity. Studies in both animal models and patients suggest that dry eye is a chronic CD4+ T cell-mediated ocular surface autoimmune-based inflammatory disease. Using a desiccating stress-induced mouse model of dry eye, we establish the fundamental role of APCs for both the generation and maintenance of ocular-specific autoreactive CD4+ T cells. Subconjunctival administration of liposome-encapsulated clodronate efficiently diminished resident ocular surface APCs, inhibited the generation of autoreactive CD4+ T cells, and blocked their ability to cause disease. APC-dependent CD4+ T cell activation required intact draining cervical lymph nodes, as cervical lymphadenectomy also inhibited CD4+ T cell-mediated dry eye disease. In addition, local depletion of peripheral conjunctival APCs blocked the ability of dry eye-specific CD4+ T cells to accumulate within the ocular surface tissues, suggesting that fully primed and targeted dry eye-specific CD4+ T cells require secondary activation by resident ocular surface APCs for maintenance and effector function. These data demonstrate that APCs are necessary for the initiation and development of experimental dry eye and support the standing hypothesis that dry eye is a self-Ag–driven autoimmune disease.

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Modulation of Integrin α4β1 (VLA-4) in Dry Eye Disease

Cited by 55 publications

References 28 publications

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

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