Abstract
Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1β and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1β. This interaction was mediated by the binding of α4β1 and αLβ2 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, α4β1 and αLβ2 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1β, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD.
Highlights
Age-related macular degeneration (AMD) is a progressive degenerative disease that leads to irreversible blindness in elderly people (Akyol and Lotery, 2020)
Retinal pigment epithelium (RPE)-toimmune cells contact and RPE apoptosis/necrosis were observed within AMD lesions (Ge-Zhi et al, 1996)
To evaluate the effects of RPE-immune cells interaction on apoptosis and necrosis, Jurkat cells were overlaid on ARPE19 cells for different time points (1, 16, 24 and 48 h); thereafter, immune cells were removed by washing with PBS and collected by centrifugation, whereas ARPE-19 cells were detached by trypsinization and centrifugated
Summary
Age-related macular degeneration (AMD) is a progressive degenerative disease that leads to irreversible blindness in elderly people (Akyol and Lotery, 2020). During ocular inflammatory process lymphocytes and macrophages are recruited to the posterior compartment of the eye and produce proinflammatory cytokines, including tumor necrosis factor α (TNFα), interleukin-1β (IL-1β) and IL-6 (Cousins et al, 2004), which play an important role in AMD pathogenesis. Adhesion molecules, such as intercellular adhesion molecules-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mediate leukocyte adhesion and recruitment to RPE. Some agents targeting integrins have already been approved for clinical practice (Raab-Westphal et al, 2017) and several new ligands are presently under development
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