Role of translocator protein (18 kDa) (TSPO) in retinal phagocytes in a mouse model of age-related macular degeneration (AMD)

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. Microglia, the resident phagocytes of the retina, play an active role in driving disease onset and progression and thus represent a broad target for therapy. Pharmacological approaches of microglia-related immunomodulation aim at dampening the harmful microglia response while preserving their homeostatic functions. The translocator protein (18kDa) (TSPO) is described as a biomarker for reactive gliosis and specific TSPO ligands have been shown to potently modulate microglia-related inflammatory responses and improved disease outcome in various preclinical model systems including Alzheimer’s, Parkinson’s, multiple sclerosis and degenerative diseases of the retina. However, the underlying molecular mechanisms of TSPO-mediated immunomodulation and its biological functions in health and disease remain elusive. In this study, 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 retinal phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are also prevented by microglia-specific TSPO knockout or XBD173 treatment. Using different NADPH oxidase (NOX)-deficient mice, we show for the first time that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. Here, TSPO regulates the Ca2+ influx from the extracellular milieu into the cytosol that is required for stimulation of NOX1 activity and expression in microglia. We also demonstrate that NOX1-derived ROS induce photoreceptor cell death in a paracrine manner and accordingly, NOX1 knockout mice show the same beneficial effects on CNV and wound healing as XBD173 treatment or microglia-specific TSPO knockout. Taken together, we showed that TSPO acts as a regulatory node and regulates microglia functions through both NOX1-dependent and independent mechanisms, defining a distinct role for TSPO in retinal phagocyte reactivity and highlights the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.