Cysteinyl leukotriene receptor 1 modulates retinal immune cells, vascularity and proteolytic activity in aged mice.

Abstract

Cysteinyl leukotrienes (CysLTs) modulate the immune response, the microvasculature, cell stress and the endosomal-lysosomal system, and are involved in cellular aging. Interestingly, CysLT receptor 1 (Cysltr1) is highly expressed in the retina, a tissue that is strongly affected by the aging process. Thus, we performed an introductory examination to determine a potential importance of Cysltr1 for cells in the neurovascular unit using qPCR and immunofluorescence analysis, and on proteolytic activity in the retinas of aged mice. Aged mice (~84 weeks) were treated orally with vehicle or 10 mg/kg montelukast (MTK), a specific Cysltr1 inhibitor, for 8 weeks, 5x/week. The retinas of young mice (~11 weeks) served as controls. Compared with young control mice, aged mice exhibited increased numbers of microglia and a reduced retinal capillary diameter, but these age-dependent changes were abrogated by MTK treatment. Retinal protein levels of the ubiquitin binding protein sequestosome-1 were amplified by aging, but were reduced by MTK treatment. Interestingly, retinal proteasome activity was decreased in aged mice, whereas Cysltr1 inhibition increased this activity. The reduction in immune cells caused by Cysltr1 suppression may dampen neuroinflammation, a known promoter of tissue aging. Additionally, an increase in capillary diameter after Cysltr1 inhibition could have a beneficial effect on blood flow in aged individuals. Furthermore, the increase in proteolytic activity upon Cysltr1 inhibition could prevent the accumulation of toxic deposits, which is a hallmark of aged tissue. Overall, Cysltr1 is a promising target for modulating the impact of aging on retinal tissue.