Research Article

Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy

See allHide authors and affiliations

Science  21 Aug 2020:
Vol. 369, Issue 6506, eaay5356
DOI: 10.1126/science.aay5356

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Remodeling senescent blood vessels

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; see also p. 919

Structured Abstract

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.

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.

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.

View Full Text

Stay Connected to Science