Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and

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M H Madeira1,2,3, K Rashid3, A F Ambrósio1,2,4

  • 1Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Scientific Reports
|February 4, 2018
PubMed

Insights

Blocking adenosine A2A receptors (A2A R) in microglia reduces inflammation and enhances photoreceptor clearance, offering a potential therapy for age-related macular degeneration (AMD). This approach targets key pathways involved in AMD pathogenesis.

Area of Science:

  • Ophthalmology
  • Neuroscience
  • Immunology

Background:

  • Age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) damage and photoreceptor loss.
  • Microglia activation, inflammasome pathways, and complement system contribute to AMD pathogenesis.
  • Adenosine A2A receptor (A2A R) blockade shows neuroprotective effects by inhibiting microglia-mediated inflammation.

Purpose of the Study:

  • To investigate if blocking A2A R in microglia can prevent AMD-associated pathological features.
  • To determine the effect of A2A R antagonism on microglial inflammatory responses and photoreceptor health.

Main Methods:

  • Used an A2A R antagonist (SCH58261) on human microglial cells and ARPE-19 cells.
  • Assessed inflammatory mediators, complement system, inflammasome activation, and photoreceptor clearance.
  • Exposed ARPE-19 cells to conditioned medium from activated microglia.

Main Results:

  • A2A R antagonist prevented upregulation of pro-inflammatory mediators and complement alterations in microglia.
  • A2A R blockade reduced inflammation, complement, and inflammasome activation in RPE cells exposed to activated microglia.
  • Blocking A2A R in microglia enhanced the clearance of apoptotic photoreceptors.

Conclusions:

  • A2A R antagonism in microglia mitigates key inflammatory pathways implicated in AMD.
  • Modulating the A2A R offers a potential therapeutic strategy for AMD by targeting microglia-RPE-photoreceptor interactions.
  • Selective A2A R antagonists may be a viable treatment for AMD.

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