Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy
François Binet, Gaël Cagnone, Sergio Crespo‐Garcia, Masayuki Hata, Mathieu Neault, Agnieszka Dejda, Ariel M. Wilson, Manuel Buscarlet, Gaëlle Mawambo, Joel P. Howard, Roberto Diaz-Marin, Célia Parinot, Vera Guber, Frédérique Pilon, Rachel Juneau, Rémi Laflamme, Christina Sawchyn, Karine Boulay, Séverine Leclerc, Afnan Abu-Thuraia, Jean‐François Côté, Grégor Andelfinger, Flávio Rezende, Florian Sennlaub, Jean‐Sébastien Joyal, Frédérick A. Mallette, Przemysław Sapieha
Abstract
In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.