Cysteinyl leukotriene receptor 1 modulates autophagic activity in retinal pigment epithelial cells

Abstract

The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. Impaired autophagy and continuous cellular stress are associated with various disorders, such as dry age-related macular degeneration (AMD), a disease for which effective therapies are lacking. Cysteinyl leukotriene receptor (CysLTR) 1 is a potential modulator of autophagy; thus, the aim of this study was to investigate the role of CysLTR1 in autophagy regulation in the RPE cell line ARPE-19. The polarized ARPE-19 monolayer exhibited expression of CysLTR1, which was colocalized with β-tubulin III. In ARPE-19 cells, autophagic activity was rhythmically regulated and was increased upon CysLTR1 inhibition by Zafirlukast (ZK) treatment. H2O2 affected the proautophagic regulatory effect of ZK treatment depending on whether it was applied simultaneously with or prior to ZK treatment. Furthermore, mRNA levels of genes related to the leukotriene system, autophagy and the unfolded protein response were positively correlated. As CysLTR1 is involved in autophagy regulation under basal and oxidative stress conditions, a dysfunctional leukotriene system could negatively affect RPE functions. Therefore, CysLTR1 is a potential target for new treatment approaches for neurodegenerative disorders, such as AMD.

Self-Assembling Tacrolimus Nanomicelles for Retinal Drug Delivery

“…D407 cells contain tight junction proteins like zonula occludens and claudins [ 48 ]. Such tight junction proteins can lower the permeation of nanocarriers and various therapeutic agents into these cells [ 49 , 50 ].…”

Chronobiological activity of cysteinyl leukotriene receptor 1 during basal and induced autophagy in the ARPE-19 retinal pigment epithelial cell line

“…The chronobiological phase of autophagic activity is influenced by extrinsic and intrinsic mechanisms at systemic and cellular levels. In agreement, polarized ARPE-19 cells exhibit varying time-dependent LC3-II levels in vitro [ 24 ]. Although the autophagic activity of cells can be influenced in vitro by exogenous stimulation, such as the addition of fresh medium, the intrinsic self-regulating mechanism has a more decisive impact [ 26 , 37 ].…”

“…Recently, we demonstrated a correlation between autophagy-/UPR-related gene expression and arachidonate 5-lipoxygenase (ALOX5) gene expression in the ARPE-19 RPE cell line [ 24 ]. The enzyme ALOX5 metabolizes arachidonic acid, which results in the formation of leukotriene A4 (LTA4), the precursor of CysLTs [ 3 ].…”

“…The enzyme ALOX5 metabolizes arachidonic acid, which results in the formation of leukotriene A4 (LTA4), the precursor of CysLTs [ 3 ]. CysLTR1 is expressed and localized to cytoskeletal microtubule structures in polarized ARPE-19 cells, and its inhibition by zafirlukast (ZTK) in the presence of lysosomal degradation inhibitors leads to increased levels of lipidated microtubule-associated protein 1 light chain 3 (LC3-II) [ 24 ], a marker of autophagic activity [ 25 , 26 ]. Moreover, microtubule structures play a key role in autophagosome and lysosome transport and are essential for the fusion of autophagy-associated organelles [ 27 – 29 ].…”

“…As CysLTR1 inhibition in polarized ARPE-19 cells has revealed the biphasic potential of CysLTR1 to regulate expression of autophagy-related genes [ 24 ], the aim of this study was to characterize the possible chronobiological activity of CysLTR1 with regard to autophagosome formation and lysosomal degradation in polarized ARPE-19 cells using the CysLTR1 antagonists ZTK and montelukast (MTK).…”