Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy

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.

Neutrophil extracellular traps, released from neutrophil, promote microglia inflammation and contribute to poor outcome in subarachnoid hemorrhage

“…In recent years, research on neutrophils in pathogen clearance, immunoregulation and disease pathology has made great progress [ 5 – 8 ]. Neutrophil extracellular traps (NETs), reticular chromatin structures, have become a new area of intense research focus in biology [ 9 – 12 ]. In an inflammatory state, NETs can cause tissue damage [ 10 , 11 , 13 – 15 ].…”

The year in basic vascular biology research: from mechanoreceptors and neutrophil extracellular traps to smartphone data and omics

“…In contrast to detrimental effects of NETs described above, a recent paper by Binet et al 39 provides evidence for a beneficial role of NETs in retinopathy. In a mouse model of ischaemic retinopathy, the researchers found that during vascular remodelling, senescent endothelial cells attracted neutrophils and triggered the extrusion of NETs by these cells.…”

“… NETs and vascular biology. Publications in 2020 found that NETs influence ( A ) ischaemic stroke, 35 ( B ) SMCs in atherosclerosis, 36 ( C ) circadian rhythm, 38 ( D ) senescent vascular cells, 39 ( E ) COVID-19 infection 40 and they can be inhibited using small polyanions 41 ( F ). Abbreviations: CCL-7, CC chemokine ligand 7; COVID-19, coronavirus disease 2019; CXCL2, C–X–C chemokine ligand 2; CXCR2, C–X–C chemokine receptor 2; ECs, endothelial cells; NETs, neutrophil extracellular traps; RBCs, red blood cells; SMCs, smooth muscle cells.…”

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions

“…To assess the role of vascular endothelial cell senescence in explaining our CRISPR screens results, we re-analyzed our RNA-seq data using senescence and SASP curated gene sets 27 . This analysis did not yield significant enrichments for sgRNAs that target DHX38 or MAT2A ( Figure 6A ).…”

“…CRISPRa at the FURIN/FES, CCDC92/ZNF664 and CNNM2 loci activates a gene expression signature of senescence. ( A ) Gene-set enrichment analyses of the five RNA-seq experiments for four curated gene sets that capture senescence or the SASP 27 . The three CRISPRa experiments are highly significant for the senescence pathways.…”