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.

Keywords: autoantigens; autoimmune diseases; autoimmunity; inflammation; neutrophil extracellular traps (NETs).

Figure 1

Neutrophil extracellular traps (NETs.) take the central stage in driving autoimmune responses. Abbreviations: AAV: Anti-neutrophil cytoplasmic antibodies associated vasculitis, ANCA: Anti-neutrophil cytoplasmic antibodies, C1q: complement factor 1q, C4: complement factor 3, C4: complement factor 4, DAMPs: damage associated molecular patterns, HMGB1: high mobility group box protein 1, IFN-α: interferon alpha, IFN-γ: interferon gamma, IL: interleukin, LL37: cathelicidin antimicrobial peptides, MSU: monosodium urate crystals, NETs: neutrophil extracellular traps, NLRP3: nucleotide-binding oligomerization domain-like receptor protein 3, RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, TLR9: toll-like receptor 9, TNF-α: tumour necrosis factor alpha.