Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy

doi:10.1126/science.aay5356

GSTDTAP > 气候变化

DOI	10.1126/science.aay5356
	Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy
	François Binet; Gael Cagnone; Sergio Crespo-Garcia; Masayuki Hata; Mathieu Neault; Agnieszka Dejda; Ariel M. Wilson; Manuel Buscarlet; Gaelle Tagne Mawambo; Joel P. Howard; Roberto Diaz-Marin; Celia Parinot; Vera Guber; Frédérique Pilon; Rachel Juneau; Rémi Laflamme; Christina Sawchyn; Karine Boulay; Severine Leclerc; Afnan Abu-Thuraia; Jean-François Côté; Gregor Andelfinger; Flavio A. Rezende; Florian Sennlaub; Jean-Sébastien Joyal; Frédérick A. Mallette; Przemyslaw Sapieha
	2020-08-21
发表期刊	Science
出版年	2020
英文摘要	The retina is a thin layer of nervous tissue at the back of the eye that transforms light into neuronal signals. The retina is essential for vision and is supported by networks of blood vessels. In diabetic retinopathy, a common cause of vision loss, these microvessels degenerate and regrow in an aberrant manner. Such degeneration and regrowth can compromise the functioning of retinal nerve cells. Binet et al. observed that, after rapid proliferation, vascular endothelial cells in diseased blood vessels engaged molecular pathways linked to cellular senescence (see the Perspective by Podrez and Byzova). Senescent vascular units summoned an inflammatory response in which neutrophils extruded neutrophil extracellular traps onto diseased vessels to remodel them. This endogenous repair mechanism promoted the elimination of senescent blood vessels and could lead to beneficial vascular remodeling. Science , this issue p. [eaay5356][1]; see also p. [919][2] ### INTRODUCTION Vision provides a critical survival advantage but requires a tight coupling between neuronal energy demands and their vascular supply. The degeneration and consequent aberrant regrowth of retinal vasculature is the hallmark of diseases such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration, which collectively are the most common causes of loss of sight in industrialized countries. Although considerable effort has been devoted to understanding how diseased blood vessels form, relatively little is known of the processes at play during late stages of pathological angiogenesis when blood vessels remodel and subsets of diseased vasculature regress. ### RATIONALE The retina is part of the central nervous system and thus has limited regenerative capacity. A relative exception to this rule are retinal blood vessels, which have a greater propensity to remodel depending on metabolic demand. We investigated the cellular mechanisms activated during the remodeling and regression of pathological blood vessels in retinopathy. We focused on a mouse model of oxygen-induced retinopathy, which has distinct and timed phases of vascular degeneration, neovascularization, and vascular regression. Our findings were verified in human patients with proliferative diabetic retinopathy. Understanding how diseased blood vessels remodel and yield functional networks has the potential to lead to strategies that enhance vascular normalization and helps to explain why retinas in certain patients have the propensity to repair themselves more readily than others. ### RESULTS We found that vascular remodeling in retinopathy is associated with bouts of sterile inflammation and tardy recruitment of neutrophils, an immune population typically associated with a first wave of invading leukocytes. We observed that, after rapid proliferation, vascular endothelial cells in diseased blood vessels engaged molecular pathways shared with aging and cellular damage that lead to cellular senescence. Senescent vascular units then released a secretome of cytokines and factors that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). Through extrusion of NETs, neutrophils eliminated diseased senescent vasculature by promoting its apoptosis. By crippling the ability of neutrophils to produce NETs by genetically removing the peptidyl arginine deiminase type IV (PAD4) enzyme, clearance of senescent cells was impaired and regression of pathological angiogenesis compromised. Similar effects were observed with the neutrophil-depleting antibody anti-Ly6G or by pharmacological inhibition of the neutrophil receptor CXCR2. ### CONCLUSION We conclude that neutrophils, through the release of NETs, targeted pathological senescent vasculature for clearance and thus prepare the ischemic retina for reparative vascular regeneration. These findings imply that elimination of senescent blood vessels leads to beneficial vascular remodeling. Although cellular senescence is not necessarily synonymous with aging, our study may provide insight into a general mechanism in which senescent endothelial cells trigger NETosis and predispose to thrombotic events such as myocardial infarction, atherosclerosis, and stroke, which are typically seen in older populations. ![Figure][3] Senescent blood vessels trigger neutrophil extracellular traps in retinopathy. ( A ) Human samples and a mouse model were used to elucidate mechanisms of vascular remodeling in retinopathy. ( B ) Upon rapid proliferation, vascular cells in pathological tufts triggered pathways of cellular senescence, leading to cytokine secretion and the recruitment of neutrophils. ( C ) Factors secreted by senescent cells triggered NETosis. ( D ) NETs promoted the removal of senescent endothelial cells, ultimately leading to regression of pathological angiogenesis and promoting the regeneration of functional vessels. 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. [1]: /lookup/doi/10.1126/science.aay5356 [2]: /lookup/doi/10.1126/science.abd7063 [3]: pending:yes
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/291210
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	François Binet,Gael Cagnone,Sergio Crespo-Garcia,et al. Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy[J]. Science,2020.
APA	François Binet.,Gael Cagnone.,Sergio Crespo-Garcia.,Masayuki Hata.,Mathieu Neault.,...&Przemyslaw Sapieha.(2020).Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy.Science.
MLA	François Binet,et al."Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy".Science (2020).