Dataset Information

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

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.

SUBMITTER: Madeira MH

PROVIDER: S-EPMC5797099 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Madeira M H MH Rashid K K Ambrósio A F AF Santiago A R AR Langmann T T

Scientific reports 20180202 1

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<sub>2A</sub> receptor (A<sub>2A</sub>R) blockade prevents microglia-mediated neuroinflammatory pro ...[more]

PMID: 29396515

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Project description:BACKGROUND AND PURPOSE: Blockade of adenosine A(2A) receptors (A(2A)R) affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL)-1?. We investigated whether A(2A)R controls the signaling of IL-1? and its deleterious effects in cultured hippocampal neurons. METHODS: Hippocampal neuronal cultures were treated with IL-1? and/or glutamate in the presence or absence of the selective A(2A)R antagonist, SCH58261 (50 nmol/l). The effect of SCH58261 on the IL-1?-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK) and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1? was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A(2A)R blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1?, was studied using single-cell calcium imaging. RESULTS: IL-1? (10 to 100 ng/ml) enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 ?g/ml), in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1? failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 ?mol/l glutamate for 25 minutes (evaluated after 24 hours). It is likely that this resulted from the ability of IL-1? to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1? alone. The selective A(2A)R antagonist, SCH58261 (50 nmol/l), prevented both the IL-1?-induced phosphorylation of JNK and p38, as well as the IL-1?-induced deregulation of calcium and the consequent enhanced neurotoxicity, whereas it had no effect on glutamate actions. CONCLUSIONS: These results prompt the hypothesis that the neuroprotection afforded by A(2A)R blockade might result from this particular ability of A(2A)R to control IL-1?-induced exacerbation of excitotoxic neuronal damage, through the control of MAPK activation and late calcium deregulation.

Dataset Information

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

Publications

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

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