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

Anne Wolf,Thomas Langmann,Michael Schramm,Marc Herb

doi:10.1038/s41467-020-16400-8

Abstract

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.

Highlights

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
Using the laser-choroidal neovascularization (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 reactive oxygen species (ROS) production in microglia is regulated by a TSPO-mediated increase in calcium levels and activation of NADPH oxidase 1 (NOX1)

Summary

Introduction

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. 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. Angiogenic growth factors including VEGF-A promote the formation of abnormal leaky blood vessels[2] and the treatment of neovascular AMD currently relies on intravitreal injections of VEGF inhibitors[3]. TSPO, together with its Müller cell-derived endogenous ligand diazepam-binding inhibitor (DBI), regulates the magnitude of microglia responses[13] Based on this concept of feedback regulation, synthetic TSPO ligands showed potent immunomodulatory and neuroprotective properties in acute light-induced retinal damage[14] and other models for Alzheimer’s disease[15], multiple sclerosis (MS)[16], and peripheral nerve injury[17]. Recent studies established global and cell-specific TSPO knockout mice to challenge the proposed role of TSPO in regulation of the mitochondrial permeability transition pore and as a gate-keeper of steroid hormone biosynthesis[22,23]

Methods

Results

Conclusion