What is it about?

Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1CreERT2:TSPOfl/fl mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.

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Why is it important?

In this study, we focus on elucidating the molecular function of TSPO in retinal immune homeostasis and angiogenesis. Using the laser-CNV model, an established system to study key aspects of neovascular AMD24, we demonstrate that microglia-specific TSPO-KO and TSPO ligand treatment strongly diminish mononuclear phagocyte reactivity and neoangiogenesis. We show that neurotoxic ROS production in microglia is regulated by a TSPO-mediated increase in calcium levels and activation of NADPH oxidase 1 (NOX1). These findings highlight a distinct role for TSPO in ROS production of phagocytes and provides a molecular mechanism for TSPO/ROS-related immunomodulatory and neuroprotective therapies in the retina and the brain.

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This page is a summary of: The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye, Nature Communications, June 2020, Springer Science + Business Media, DOI: 10.1038/s41467-020-16400-8.
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