Activated αvβ3 Integrin Regulates αvβ5 Integrin–Mediated Phagocytosis in Trabecular Meshwork Cells

Gagen, Debjani; Filla, Mark S.; Clark, Ross; Liton, Paloma B.; Peters, Donna M.

doi:10.1167/iovs.13-12084

Cited by 49 publications

(78 citation statements)

References 46 publications

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“…We also found that pre-treatment of cells with an ␣V␤5 function-blocking antibody significantly reduces phagocytosis by lens epithelial cells (Fig. 7) consistent with the established function of ␣V␤5 for phagocytosis in other tissues, including the retinal pigmented epithelium (46,(55)(56)(57) and trabecular meshwork (85). Finally, we demonstrate that exposure of lens epithelial cells to UVA light results in degradation of ␣V␤5 and reduced lens epithelial cell phagocytosis (Fig.…”

Section: Discussionsupporting

confidence: 84%

Integrin αVβ5-mediated Removal of Apoptotic Cell Debris by the Eye Lens and Its Inhibition by UV Light Exposure

Chauss

Brennan

Бакина

et al. 2015

Journal of Biological Chemistry

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Accumulation of apoptotic material is toxic and associated with cataract and other disease states. Identification of mechanisms that prevent accumulation of apoptotic debris is important for establishing the etiology of these diseases. The ocular lens is routinely assaulted by UV light that causes lens cell apoptosis and is associated with cataract formation. To date, no molecular mechanism for removal of toxic apoptotic debris has been identified in the lens. Vesicular debris within lens cells exposed to UV light has been observed raising speculation that lens cells themselves could act as phagocytes to remove toxic apoptotic debris. However, phagocytosis has not been confirmed as a function of the intact eye lens, and no mechanism for lens phagocytosis has been established. Here, we demonstrate that the eye lens is capable of phagocytizing extracellular lens cell debris. Using high throughput RNA sequencing and bioinformatics analysis, we establish that lens epithelial cells express members of the integrin ␣V␤5-mediated phagocytosis pathway and that internalized cell debris co-localizes with ␣V␤5 and with RAB7 and Rab-interacting lysosomal protein that are required for phagosome maturation and fusion with lysosomes. We demonstrate that the ␣V␤5 receptor is required for lens epithelial cell phagocytosis and that UV light treatment of lens epithelial cells results in damage to the ␣V␤5 receptor with concomitant loss of phagocytosis. These data suggest that loss of ␣V␤5-mediated phagocytosis by the eye lens could result in accumulation of toxic cell debris that could contribute to UV light-induced cataract formation.

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Section: Discussionsupporting

confidence: 84%

Integrin αVβ5-mediated Removal of Apoptotic Cell Debris by the Eye Lens and Its Inhibition by UV Light Exposure

Chauss

Brennan

Бакина

et al. 2015

Journal of Biological Chemistry

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“…For functional follow-up, the human anterior segment perfusion model, which recapitulates outflow regulation in vivo (Johnson and Tschumper, 1987), has been employed. Many of the changes seen in the trabecular meshwork of human eyes treated with glucocorticoids are also seen in eyes perfused with glucocorticoids in vitro (Clark et al, 1995b) and can be mimicked in cultured trabecular meshwork cells (Filla et al, 2011; Gagen et al, 2014; Gagen et al, 2013). This provides evidence for a direct action of glucocorticoids on the trabecular meshwork (rather than a systemic action).…”

Section: Cell Biologymentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

126

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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“…αVβ5 integrin is able to bind and internalize apoptotic cells via Rac1 activation [13, 14]. In trabecular meshwork cells, αVβ5 integrin mediates phagocytosis via FAK activation, while αVβ3 reduces phagocytotic activity in these cells [15]. In contrast, αVβ3 serves to internalize apoptotic neutrophils in macrophages [13].…”

Section: Introductionmentioning

confidence: 99%

Expression of the Alpha8 Integrin Chain Facilitates Phagocytosis by Renal Mesangial Cells

Marek¹,

Becker²,

Fahlbusch³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC. Methods: MC were isolated from wild type (WT) and Itga8-/- mice. Latex beads were coated with matrix components. Apoptosis was induced by cisplatin in macrophages and in DiI-stained MC. After coincubation of latex beads or apoptotic cells with MC, the phagocytosis rate was detected in WT and Itga8-/- MC via fluorescence microscopy and FACS analysis. Results: Itga8-/- MC showed reduced phagocytosis of matrix-coated beads and apoptotic cells compared to WT MC. Reduction of stress fibers was observed in Itga8-/- compared to WT MC. Inhibition of cytoskeletal reorganization by inhibition of Rac1 or ROCK during phagocytosis significantly decreased the rate of phagocytosis by WT MC but not by Itga8-/- MC. Conclusion: The expression of Itga8 facilitates phagocytosis in MC, likely mediated by Itga8-cytoskeleton interactions. An impairment of MC phagocytosis might thus contribute to a delayed glomerular regeneration in Itga8-/- mice.

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Activated αvβ3 Integrin Regulates αvβ5 Integrin–Mediated Phagocytosis in Trabecular Meshwork Cells

Cited by 49 publications

References 46 publications

Integrin αVβ5-mediated Removal of Apoptotic Cell Debris by the Eye Lens and Its Inhibition by UV Light Exposure

Integrin αVβ5-mediated Removal of Apoptotic Cell Debris by the Eye Lens and Its Inhibition by UV Light Exposure

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Expression of the Alpha8 Integrin Chain Facilitates Phagocytosis by Renal Mesangial Cells

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