CD73 controls ocular adenosine levels and protects retina from light-induced phototoxicity

Abstract

ATP and adenosine have emerged as important signaling molecules involved in vascular remodeling, retinal functioning and neurovascular coupling in the mammalian eye. However, little is known about the regulatory mechanisms of purinergic signaling in the eye. Here, we used three-dimensional multiplexed imaging, in situ enzyme histochemistry, flow cytometric analysis, and single cell transcriptomics to characterize the whole pattern of purine metabolism in mouse and human eyes. This study identified ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), NTPDase2, and ecto-5′-nucleotidase/CD73 as major ocular ecto-nucleotidases, which are selectively expressed in the photoreceptor layer (CD73), optic nerve head, retinal vasculature and microglia (CD39), as well as in neuronal processes and cornea (CD39, NTPDase2). Specifically, microglial cells can create a spatially arranged network in the retinal parenchyma by extending and retracting their branched CD39high/CD73low processes and forming local “purinergic junctions” with CD39low/CD73− neuronal cell bodies and CD39high/CD73− retinal blood vessels. The relevance of the CD73–adenosine pathway was confirmed by flash electroretinography showing that pharmacological inhibition of adenosine production by injection of highly selective CD73 inhibitor PSB-12489 in the vitreous cavity of dark-adapted mouse eyes rendered the animals hypersensitive to prolonged bright light, manifested as decreased a-wave and b-wave amplitudes. The impaired electrical responses of retinal cells in PSB-12489-treated mice were not accompanied by decrease in total thickness of the retina or death of photoreceptors and retinal ganglion cells. Our study thus defines ocular adenosine metabolism as a complex and spatially integrated network and further characterizes the critical role of CD73 in maintaining the functional activity of retinal cells.

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

“…In the mammalian retina, ATP and adenosine ( ADO ) are crucial molecules that participate in vascular remodeling and form the neurovascular coupling ( Zeiner et al, 2019 ; Losenkova et al, 2022 ). Abnormally elevated expression of ATP is a common phenomenon in many retinopathies.…”

“…Interestingly, microglia create a spatially arranged network in the retinal parenchyma and form a local “purinergic junctions” system with CD39 low /CD73 − neuronal cell bodies and CD39 high /CD73 − retinal blood vessels through their CD39 high /CD73 low branches ( Losenkova et al, 2022 ). Further exploring the mechanisms through which a broad spectrum of soluble and membrane-binding enzymes synergistically regulates purine levels in the retina may serve as potential therapeutic targets for the treatment of retinopathy ( Zeiner et al, 2019 ).…”

Melanopsin-mediated optical entrainment regulates circadian rhythms in vertebrates

“…Recent studies have shown that adenylyl cyclase 2 and cAMP mediate the phototransduction of OPN4 in M4-subtype ipRGCs 24 . Considering the ability of retinal adenosine to influence photosensitive electrophysiological activity in the retina 79 , the effect of cAMP on OPN4 phototransduction cannot be ignored. Admittedly, OPN4-mediated phototransduction mechanisms have also been implicated in species that involve G i/o (human, mouse, and amphioxus), Gs (chicken), or Gt (chicken) activity 26 , 47 , 80 .…”