The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye

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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Photo by Victor Freitas on Unsplash

Photo by Victor Freitas on Unsplash

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.