Neutrophil Extracellular Traps in the Autoimmunity Context

Abstract

The formation of neutrophil extracellular traps (NETs) is a strategy utilized by neutrophils for capturing infective agents. Extracellular traps consist in a physical net made of DNA and intracellular proteins externalized from neutrophils, where bacteria and viruses are entrapped and killed by proteolysis. A complex series of events contributes to achieving NET formation: signaling from infectious triggers comes first, followed by decondensation of chromatin and extrusion of the nucleosome components (DNA, histones) from the nucleus and, after cell membrane breakdown, outside the cell. NETs are composed of either DNA or nucleosome proteins and hundreds of cytoplasm proteins, a part of which undergo post-translational modification during the steps leading to NETs. There is a thin balance between the production and the removal of circulating NETs from blood where digestion of DNA by circulating DNases 1 and IL3 has a critical role. A delay in NET removal may have consequences for autoimmunity. Recent studies have shown that circulating NET levels are increased in systemic lupus erythematosus (SLE) for a functional block of NET removal mediated by anti-DNase antibodies or, in rare cases, by DNase IL3 mutations. In SLE, the persistence in circulation of NETs signifies elevated concentrations of either free DNA/nucleosome components and oxidized proteins that, in some cases, are recognized as non-self and presented to B-cells by Toll-like receptor 9 (TLR9). In this way, it is activated as an immunologic response, leading to the formation of IgG2 auto-antibody. Monitoring serum NET levels represents a potential new way to herald the development of renal lesions and has clinical implications. Modulating the balance between NET formation and removal is one of the objectives of basic research that are aimed to design new drugs for SLE. Clinical Trial Registration Number: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).

Keywords: Lupus nephritis; anti-C1q antibodies; anti-alpha enolase; anti-histone; biomarker; systemic lupu erythematosus.

Figure 1

Traditional immunofluorescence microscopy analysis of neutrophil extracellular trap (NET) filaments showing that αenolase and DNA are intensely present in NET filaments and co-localized in large segments. The images were acquired using LSM 510 Meta confocal system scan.

Figure 2

Schematic representation of the pathway that potentially connects neutrophil extracellular traps (NETs) with the formation of antibodies of IgG2 isotype in systemic lupus erythematosus. The various steps are detailed in the text. As for the last step that involves TLR9, the data supporting a direct link between NETs and IgG2 via TLR9 are presented in this special issue of Frontiers (The kidney in inflammatory and immune-mediated diseases) (see Bertelli et al.).