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

• DOI: 10.1038/s41467-020-16400-8
• Publication Date: 2020-06-01T10:03:14Z
• Authors: Anne Wolf; Marc Herb; Michael Schramm; Thomas Langmann
• Keywords: Mice, Knockout; 0301 basic medicine; Phagocytes; Neovascularization, Pathologic; Science; Q; Mice, Transgenic; Article; Cell Line; Mice, Inbred C57BL; 03 medical and health sciences; Gene Expression Regulation; Receptors, GABA; Purines; NADPH Oxidase 1; Wet Macular Degeneration; Animals; Microglia; Reactive Oxygen Species; Signal Transduction

AbstractAberrant 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.