Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Abstract

Objective— An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. Approach and Results— Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell–cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. Conclusions— These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

“…Insufficient regulation of NE activity by A1AT importantly contributes to endothelial damage during acute lung injury (36) and nephritis (37) and also promotes tumor progression (38). Although A1AT is able to inhibit both NE released to the pericellular space and membranebound NE (39), restricted accessibility of plugged or condensed areas might lower the capacity of inhibition (40) and limit the efficacy of NE inhibition as a therapy for conditions such as cystic fibrosis (41).…”

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…In addition, subclinical kidney injury may readily be missed until consecutive exposures to UV light compound the effects. While we found that neutrophil-mediated kidney inflammation in response to UV light does not cause clinical disease in healthy mice, such a mechanism may contribute to LN flares in photosensitive lupus patients in multiple ways: Fc receptor engagement by immune complexes could enhance neutrophil recruitment resulting in ROS and protease release 105,106 ; the heightened capacity of lupus neutrophils and LDGs to produce NETs, which in SLE patients are not cleared efficiently 107,108 , could lead to release of tissue-damaging proteases 109,110 , propagation of the IFN-I response 85,86 , or direct damage to the kidney endothelium by creating vascular damage and leakage 14,111 . Moreover, the underlying differences in lupus skin, such as enhanced IFN-I signaling 7,112,113 and defects in protective Langerhans cell population 114 could inform the extent and nature of neutrophil-mediated systemic responses.…”

Networks that stop the flow: A fresh look at fibrin and neutrophil extracellular traps

“…Underlining the role of endothelium in thrombus resolution, during the process of angiophagy, the endothelium engulfs clots up to a certain size, as demonstrated in an elegant study by Lam et al [131]. Similarly, endothelial cells have been recently shown capable of phagocytosing NETs to a certain extent [132].…”