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

Summary: This study 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.

The MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Experimentica Research & Development division in Lithuania and Finland, the Department of Ophthalmology, Loyola University Chicago, Stritch School of Medicine, the Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, published about the ocular adenosine metabolism as a complex and spatially integrated network and the critical role of CD73 in maintaining the functional activity of retinal cells.

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 CD39^high/CD73^low processes and forming local “purinergic junctions” with CD39^low/CD73⁻ neuronal cell bodies and CD39^high/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.

Authors:  Karolina Losenkova | Akira Takeda | Symantas Ragauskas | Marc Cerrada-Gimenez | Maria Vähätupa | Simon Kaja | Marius L. Paul | Constanze C. Schmies | Georg Rolshoven | Christa E. Müller | Jouko Sandholm | Sirpa Jalkanen | Giedrius Kalesnykas | Gennady G. Yegutkin

Keywords: NTPDase1/CD39, Ecto-5′-nucleotidase/CD73, Adenosine receptors, Mouse and human retina