Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses

Abstract

Following fifteen years of research, neutrophil extracellular traps (NETs) are widely reported in a large range of inflammatory infectious and non-infectious diseases. Cumulating evidences from in vitro, in vivo and clinical diagnostics suggest that NETs may play a crucial role in inflammation and autoimmunity in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Most likely, NETs contribute to breaking self-tolerance in autoimmune diseases in several ways. During this review, we discuss the current knowledge on how NETs could drive autoimmune responses. NETs can break self-tolerance by being a source of autoantigens for autoantibodies found in autoimmune diseases, such as anti-citrullinated protein antibodies (ACPAs) in RA, anti-dsDNA in SLE and anti-myeloperoxidase and anti-protein 3 in AAV. Moreover, NET components could accelerate the inflammatory response by mediating complement activation, acting as danger-associated molecular patterns (DAMPs) and inflammasome activators, for example. NETs also can activate other immune cells, such as B cells, antigen-presenting cells and T cells. Additionally, impaired clearance of NETs in autoimmune diseases prolongs the presence of active NETs and their components and, in this way, accelerate immune responses. NETs have not only been implicated as drivers of inflammation, but also are linked to resolution of inflammation. Therefore, NETs may be central regulators of inflammation and autoimmunity, serve as biomarkers, as well as promising targets for future therapeutics of inflammatory autoimmune diseases.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

“…In addition, it was found that NETs engulfed by fibroblasts stimulated formation of the antibodies against citrullinated histones in the RA model [ 105 ]. Similar observations indicate involvement of NETosis in the autoimmune diseases, such as vasculitis associated with “anti-neutrophil antibodies” (AAV), antiphospholipid syndrome, multiple sclerosis, and psoriasis (see review [ 106 ]). Interestingly, in some diseases, NETosis can play an anti-inflammatory role.…”

Characterization of Bovine Neutrophil Extracellular Traps Induced by Histamine

“…Initially, most of studies were focused on microorganisms-triggered NETs. As a vast number of molecules were identi ed as NETs stimuli such as ionomycin [34], nicotine [35], hydrogen peroxide [11], TNF-α [36], Fc receptors [13], IFN-γ [37], and antimicrobial peptides [38], increasing studies are paying attention on non-infectious and autoimmune diseases [39,40]. Histamine is a main mediator in allergic diseases, and we found it also can induce NET formation.…”

Neutrophils and Neutrophil Extracellular Traps Regulate Immune Responses in Health and Disease

“…Consistent with this, Fousert et al also propose NETs as promising biomarkers for autoimmune diseases since they contribute to the development of autoimmunity by breaking self-tolerance [22]. They further conclude that therapeutics targeted at neutrophils and NETs will be beneficial for the treatment of inflammatory autoimmune diseases [22].…”