Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro.
Maria Helena MadeiraK RashidAntónio Francisco AmbrósioAna Raquel SantiagoThomas LangmannPublished in: Scientific reports (2018)
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.
Keyphrases
- inflammatory response
- age related macular degeneration
- neuropathic pain
- lipopolysaccharide induced
- induced apoptosis
- lps induced
- cell cycle arrest
- toll like receptor
- oxidative stress
- endothelial cells
- cell death
- poor prognosis
- spinal cord
- endoplasmic reticulum stress
- single cell
- mouse model
- spinal cord injury
- binding protein
- induced pluripotent stem cells
- mesenchymal stem cells
- stem cells
- cell proliferation
- long non coding rna
- cell therapy
- pi k akt