Abstract
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 A2A receptor (A2AR) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A2AR in microglia protects against the pathological features of AMD. Herein, we show that an A2AR 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 A2AR 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 A2AR in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A2AR antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors.
Highlights
Age-related macular degeneration (AMD) is a major cause of vision loss worldwide and the leading cause of blindness in the elderly in developed countries[1]
We firstly investigated whether the incubation of human microglial cells with Zymosan and phorbol myristate acetate (PMA), two potent pro-inflammatory stimuli[28], would be able to increase the levels of extracellular adenosine, which could boost A2A receptor (A2AR) activation, and affect A2AR expression
These results demonstrate that pro-inflammatory conditions can trigger an increase in the release of adenosine from human microglia that may signal through the upregulated A2AR
Summary
Age-related macular degeneration (AMD) is a major cause of vision loss worldwide and the leading cause of blindness in the elderly in developed countries[1]. Microglia reactivity is involved in the recruitment and activation of complement system[7,8] and inflammasome pathways[9], which may contribute to photoreceptor degeneration[10]. The complement system and inflammasome pathways, key innate immune defenses against inflammation, orchestrate critical responses in the CNS. A2E, a RPE lipofuscin and drusen component, triggers microglia reactivity and complement activation www.nature.com/scientificreports/. There is evidence showing the ability of drusen to induce the activation of inflammasome, namely NLRP3 inflammasome, in retinal mononuclear cells[20]. Inflammasome has been detected in the RPE, in both dry and wet AMD, and might contribute to RPE degeneration[21,22]. Factors released from reactive microglia can induce the activation of NLRP3 inflammasome in ARPE-19 cells[9]
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