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.
Highlights
Known as one of the first responder cells of the innate immune system, neutrophils are described as phagocytes in textbooks that are involved in initial early host-defence responses during infection/injury.the discovery of neutrophil extracellular traps (NETs) has shifted the paradigm of our current understanding of neutrophil functions, and their significance during immune responses, quite drastically
Evidences from different in vitro and in vivo studies currently support a theory of what we propose to be a ‘vicious loop of inflammation and autoimmunity’
Neutrophil Extracellular Traps (NETs) formation itself was found to be dependent on noncanonical inflammasome activation, as extrusion of NETs by neutrophils exposed to lipopolysaccharide (LPS) or Gram-negative bacteria relied on activated caspase11 and activated gasdermin D (GSDMD) [60,61]
Summary
Known as one of the first responder cells of the innate immune system, neutrophils are described as phagocytes in textbooks that are involved in initial early host-defence responses during infection/injury. LN patient-derived PMA–NETs presented a high expression of α-enolase and annexin A1, compared to SLE PMA–NETs and healthy neutrophils Accompanying these contradicting findings, it is important to take into account that most of these in vitro NETome studies are performed using non-physiological stimuli such as PMA or calcium ionophore A23187 [10,15]. NET-associated MPO and proteinase 3 (PR3) enzymes as major autoantigenic targets of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); NET-derived extracellular nucleic acids and dsDNA as the targets of SLE autoantibodies; citrullinated proteins namely citrullinated histones as neoepitopes for anti-citrullinated protein antibodies (ACPA) in RA [16,17,18] These NET-associated autoantigens and their contribution are discussed in a disease-specific manner below.
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