At the Bench: Neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases

Abstract

The putative role of neutrophils in host defense against pathogens is a well-recognized aspect of neutrophil function. The discovery of neutrophil extracellular traps has expanded the known range of neutrophil defense mechanisms and catalyzed a discipline of research focused upon ways in which neutrophils can shape the immunologic landscape of certain autoimmune diseases, including systemic lupus erythematosus. Enhanced neutrophil extracellular trap formation and impaired neutrophil extracellular trap clearance may contribute to immunogenicity in systemic lupus erythematosus and other autoimmune diseases by promoting the externalization of modified autoantigens, inducing synthesis of type I IFNs, stimulating the inflammasome, and activating both the classic and alternative pathways of the complement system. Vasculopathy is a central feature of many autoimmune diseases, and neutrophil extracellular traps may contribute directly to endothelial cell dysfunction, atherosclerotic plaque burden, and thrombosis. The elucidation of the subcellular events of neutrophil extracellular trap formation may generate novel, therapeutic strategies that target the innate immune system in autoimmune and vascular diseases.

Keywords: ANCA-associated vasculitis; atherosclerosis; systemic lupus erythematosus; thrombosis.

Figure 1.. Immunofluorescence microscopy demonstrating NET formation.

LDGs isolated from a patient with SLE undergo spontaneous NET formation. NETs are visualized by confocal microscopy as wispy strands of DNA decorated with neutrophil granular proteins (blue, Hoechst stain for DNA; red, MPO). Image courtesy of Carmelo Carmona-Rivera, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, U.S. National Institutes of Health.

Figure 2.. Overview of NETs involvement in autoimmunity and vasculopathy.

Neutrophils (PMNs) release NETs with potential immunogenic roles. Protein-DNA complexes within NETs (e.g., LL-37/DNA) activate pDCs to synthesize TIIFNs. NETs interact with B and T lymphocytes, linking the innate and adaptive immune systems and promoting their activation. NETs can activate platelets and coagulation factors and promote thrombosis. NET contents are potentially toxic to endothelial cells (EC), promoting vasculopathy and apoptosis through MMPs and histones. Several amplification loops of NETosis exist, whereby products found within NETs (autoantigens, complement activating factors, proinflammatory cytokines) or antibodies (Abs) and immune complexes (ICs) to/containing NET-related proteins stimulate neutrophils to undergo NET formation. In a feed-forward loop, NET proteins stimulate the inflammasome (NLRP3) in macrophages (Mϕ) with resultant release of proinflammatory cytokines (IL-1 and IL-18) that promote additional NET formation in granulocytes.