Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro

Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A(2A) receptor (A(2A)R) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A(2A)R in microglia protects against the pathological features of AMD. Herein, we show that an A(2A)R antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A(2A)R in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A(2A)R in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A(2A)R antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors.