Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients develop autoantibodies to DNA, histones, and often to neutrophil proteins. These form immune complexes that are pathogenic and may cause lupus nephritis. In SLE patients, infections can initiate flares and are a major cause of mortality. Neutrophils respond to infections and release extracellular traps (NETs), which are antimicrobial and are made of DNA, histones, and neutrophil proteins. The timely removal of NETs may be crucial for tissue homeostasis to avoid presentation of self-antigens. We tested the hypothesis that SLE patients cannot clear NETs, contributing to the pathogenesis of lupus nephritis. Here we show that serum endonuclease DNase1 is essential for disassembly of NETs. Interestingly, a subset of SLE patients’ sera degraded NETs poorly. Two mechanisms caused this impaired NET degradation: ( i ) the presence of DNase1 inhibitors or ( ii ) anti-NET antibodies prevented DNase1 access to NETs. Impairment of DNase1 function and failure to dismantle NETs correlated with kidney involvement. Hence, identification of SLE patients who cannot dismantle NETs might be a useful indicator of renal involvement. Moreover, NETs might represent a therapeutic target in SLE.

Increased IgG on cell‐derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation

“…Consequently, the proportion of circulating cell-derived MPs with surface-bound IgG was significantly increased in the SLE group (median [5th-95th percentile] 3.5% [0. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].3%] in the SLE patient group versus 0.4% [0.02-4.3%] in the healthy control group; P Ͻ 0.0001).…”

“…This would lead to an increased half-life of MPs and thus an accumulation of circulating cellular remnants (14). It was recently proposed that a similar autoantibody-mediated mechanism may interfere with the degradation of neutrophil extracellular traps in subsets of SLE patients (8). However, recent studies have not shown increased levels of MPs in SLE patients (13).…”

Changing world of neutrophils

“…Activation of platelets via TLR2 and TLR4 receptors [101] and degradation of coagulation inhibitory proteins by proteases on the surface of NETs both promote blood clotting which also impairs bacterial dissemination [51,69]. On the other hand, formation of NETs was suggested to contribute to the viscosity of bronchial fluid in cystic fibrosis patients [67], to formation of autoantibodies in systemic lupus erythematosus [44] and to the pathogenesis of autoimmune vasculitis [54]. Most recently, the presence of NETs was demonstrated in atherosclerotic plaques in murine carotid arteries and in human tissues removed by endarterectomy [72] substantiating the involvement of neutrophils in atherogenesis.…”

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

“…The newly discovered form of neutrophil cell death, NETosis, in which neutrophils throw out chromatin fibers (neutrophil extracellular traps; NETs) containing antibacterial peptidesand nuclear antigens, have been implicated in the SLE pathogenesis [121]. Increased NETosis [122] of SLE patients, as well as reduced capacity to degrade NETs have been demonstrated in vitro [123,124]. It has also been suggested that dysfunctional neutrophils can contribute to organ damage [121].…”