Clinical Implications of Excessive Neutrophil Extracellular Trap Formation in Renal Autoimmune Diseases

Abstract

Neutrophil extracellular traps (NETs) are extracellular DNA structures covered with antimicrobial peptides, danger molecules, and autoantigens that can be released by neutrophils. NETs are an important first-line defense mechanism against bacterial, viral, fungal, and parasitic infections, but they can also play a role in autoimmune diseases. NETs are immunogenic and toxic structures that are recognized by the autoantibodies of patients with antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) (i.e., against myeloperoxidase or proteinase-3) and systemic lupus erythematosus (SLE) (i.e., against double-stranded DNA, histones, or nucleosomes). There is cumulating preclinical and clinical evidence that both excessive formation and impaired degradation of NETs are involved in the pathophysiology of AAV and SLE. These autoimmune diseases give rise to 2 clinically and pathologically distinct forms of glomerulonephritis (GN), respectively, crescentic pauci-immune GN and immune complex-mediated GN. Therefore, it is relevant to understand the different roles NET formation can play in the pathophysiology of these most prevalent renal autoimmune diseases. This review summarizes the current concepts on the role of NET formation in the pathophysiology of AAV and SLE, and provides a translational perspective on the clinical implications of NETs, such as potential therapeutic approaches that target NET formation in these renal autoimmune diseases.

Keywords: ANCA-associated vasculitis; autoimmune diseases; glomerulonephritis; neutrophil extracellular traps (NETs); systemic lupus erythematosus.

Figure 1

Ex vivo neutrophil extracellular trap (NET) formation in antineutrophil cytoplasmic antibodies (ANCA)−associated vasculitis (AAV) and systemic lupus erythematosus (SLE). Paul-Karl-Horan (PKH)26-labelled neutrophils (red) derived from a healthy donor were exposed to 10% serum of patients with AAV or SLE for 4 hours to induce NET formation. Extracellular DNA was stained with SYTOXgreen (green) and NET formation was imaged with immunofluorescence confocal microscopy. Images of AAV- (a) and SLE-induced (b) NET formation are shown at original magnification ×10; bar = 20 um.

Figure 2

Overview of neutrophil extracellular trap (NET) formation in antineutrophil cytoplasmic antibodies (ANCA)−associated vasculitis (AAV) versus systemic lupus erythematosus (SLE). In AAV, lytic NET formation is induced involving reduced NAD phosphate oxidase and protein arginine deiminase (PAD) enzymes, which results in a lytic expulsion of NETs harboring citrullinated histones within hours. In SLE, nonlytic extrusion of NETs concomitant with clustering of neutrophils is induced within minutes. SLE-induced NETs have immunogenic properties, including enrichment for High Mobility Group Box Protein 1 (HMGB1), oxidized mitochondrial-derived DNA, and immune complex (ICx) formation, which was not the case for AAV-induced NETs. ROS, reactive oxygen species.