NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis

By R. Khandpur, C. Carmona-Rivera, Anuradha Vivekanandan-Giri, Alison M. Gizinski, S. Yalavarthi, J. Knight, Sean C Friday, Sam Li, Rajiv M. Patel, V. Subramanian and 5 more. Science Translational Medicine, 2013

1,315 citations recorded by the source corpus.

Neutrophil NETs may contribute to pathogenesis of rheumatoid arthritis. Autoantigens Slip Through the NET Autoimmune diseases are caused when the body’s immune system attacks the very tissues it’s supposed to protect. Yet, what exactly induces this loss of tolerance to self remains murky. For some autoimmune diseases, autoantigens—cellular targets of the immune response—have been identified, although it remains unclear how these normally intracellular proteins are exposed to the immune response. One hypothesis as to how these proteins may be externalized is through the excretion of neutrophil extracellular traps (NETosis). NETosis is thought to be involved in neutrophil response to bacteria, but the secretion of self-antigens in the context of inflammatory stimuli may boost autoimmune response. Now, Khandpur et al. look at the role of NETosis in rheumatoid arthritis. Autoantibodies to citrullinated antigens (ACPAs) are thought to be pathogenic in rheumatoid arthritis. The authors observed increased NETosis in patients with rheumatoid arthritis compared with both healthy controls and patients with non-autoimmune osteoarthritis. Indeed, NETosis correlated with levels of ACPA, and ACPA actually altered the makeup of the proteins secreted by neutrophils. NETs from rheumatoid arthritis patients contained citrullinated proteins, and these NETs enhanced the inflammatory response in fibroblasts from inflamed joints. Thus, altered NETosis in rheumatoid arthritis patients may contribute to the pathogenesis of disease. The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti–citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor–α (TNF-α) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.

Subfields: Immunology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/7518aa565cd0ab051b0267eaf35475254b0774be

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Citations in the corpus

• A Myeloperoxidase-Containing Complex Regulates Neutrophil Elastase Release and Actin Dynamics during NETosis (2014, neutral): “…of NET degradation is linked to several diseases, including cystic fibrosis, preeclampsia, autoimmunity, and vascular diseases (Garcia-Romo et al., 2011; Hakkim et al., 2010; Kessen-brock et al., 2009; Khandpur et al., 2013; Lande et al., 2011; Papayannopoulos et al., 2011; Villanueva et al., 2011).”
• Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “…of neutrophils in atherosclerosis), and NETs have also been suggested to participate in the pathogenesis of rheumatoid arthritis by displaying citrullinated autoantigens in an inflammatory environment (Khandpur et al., 2013), further extending the importance of such a pathway in human diseases.”
• NETosis: how vital is it? (2013, background): “Moreover, NETosis resulted in the externalization of citrullinated autoantigens, thereby linking NET formation to RA.27”
• Inflammation and aging: signaling pathways and intervention therapies (2023, background): “In RA, the disease pathology is characterized by the accumulation of DNA-MPO complexes and the presence of antibodies targeting guanylated histones (NETosis markers).(261,262) In myocarditis, NETosis probably promotes PMN trafficking via MK and substantially contributes to cardiac inflammation.”
• Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “Although NET generation has been described initially as an antimicrobial mechanism, recent data suggest that NETs could play a more important role in autoimmune and autoinflammatory pathologies, such as vasculitis [71], lung injury [72,73], atherosclerosis [74], rheumatoid arthritis [75,76], thrombo”
• Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “For this purpose, the deployment of anti-CXCR2 antibodies to deplete TANs or the targeting of specific neutrophil-derived or recruiting chemokines, such as CXCL-5, Gro-𝛼, or IL-8, was performed and reported to be successful [59].”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “…patients were also reported to readily form NETs (Villanueva et al., 2011), and because these NETs presented autoantigens, it has been suggested that LDNs in these patients are responsible for sustaining chronic inflammation leading to autoimmunity (Garcia-Romo et al., 2011; Khandpur et al., 2013).”
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “The synovial fluid at the synovial cavity of RA patients becomes infiltrated with neutrophils that readily form NETs; furthermore, even the circulating neutrophils of RA patients are more easily stimulated to NETosis than those from healthy subjects (144, 145).”
• Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies (2018, background): “ACPAs induce NETosis and in turn NETosis provides citrullinated autoantigens.(38) EBV can affect ACPA-producing B cells and impaired EBV control can be observed in RA.”