+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Neutrophil extracellular traps exert both pro- and anti-inflammatory actions in rheumatoid arthritis that are modulated by C1q and LL-37



Neutrophil extracellular traps exert both pro- and anti-inflammatory actions in rheumatoid arthritis that are modulated by C1q and LL-37



Journal of Autoimmunity 2019



Neutrophil extracellular traps (NET), produced by activated polymorphonuclear neutrophils (PMN), are supposed to play a role in the pathogenesis of rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). Indeed, NET contain citrullinated autoantigens and some RA autoantibodies recognize NET. However, the mechanisms by which NET trigger or perpetuate the inflammatory process in RA are hitherto not elucidated. We hypothesized that, in addition to citrullination, NET might also contain stimulatory proteins and directly activate inflammatory target cells, as PMN and macrophages. NET antigenic and inflammatory properties were analyzed in 157 healthy donors (HD) and RA patients, the largest analysis reported so far. Primary PMN and monocyte-derived macrophages were isolated and immunoglobulin G (IgG) purified. NET were induced (NETosis), isolated and quantified. NET antigenicity was analyzed by fluorescence microscopy. PMN and macrophages were stimulated with NET with/without ACPA, C1q, LL-37 or lipopolysaccharide (LPS) and cell activation was estimated by flow cytometry and ELISA. PMN from RA patients produced more NET than HD PMN. We next dissected how NET mechanistically affect inflammatory cells. Particularly, we show for the first time that RA and HD NET activated both resting macrophages and PMN, but importantly RA NET were more stimulatory, leading to secretion of inflammatory cytokines and up-regulation of HLA/CD86/CD11b. IgG from ACPA-positive RA patients specifically recognized RA and even HD NET. Nevertheless, NET-induced cell activation occurs independently of immune complex formation with ACPA. Likewise, endosomal acidification was not required. Notably, we also report that complement C1q increased the NET stimulatory activity on macrophages only, due to higher expression of C1q receptors, which was further supported by the LL-37 antimicrobial peptide. In contrast, NET specifically inhibited interleukin (IL)-6 secretion by LPS-activated macrophages and not PMN, especially with C1q/LL-37. This inhibition was not mediated by NET-derived proteases or LPS neutralization and was associated with the simultaneous induction of IL-10 secretion. We show that NET possess both pro- and anti-inflammatory properties depending on target cells, their activation levels and C1q/LL-37. Thus, independently of ACPA, NET modulate RA chronic inflammation via this new dual activity we identified. In addition, NET may trigger autoimmunity in RA as ACPA recognize NET antigens but not non-activated PMN. Therefore, we conclude that excess of NETosis together with enhanced NET activity participate to RA pathogenesis at different levels.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 066446997

Download citation: RISBibTeXText

PMID: 30704942

DOI: 10.1016/j.jaut.2019.01.003


Related references

A1.29Normal and rheumatoid arthritis neutrophil extracellular Traps are both pro- and anti-inflammatory via mechanisms involving the C1Q complement protein but independently of Acpa, ll-37 or the inflammasome. Annals of the Rheumatic Diseases 75(Suppl 1): A12.2-A13, 2016

Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients. Arthritis and Rheumatology 69(6): 1165-1175, 2017

DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thrombosis and Haemostasis 113(6): 1289-1298, 2016

OP0310Association of Neutrophil Extracellular Traps with Atherosclerosis in Rheumatoid Arthritis. Annals of the Rheumatic Diseases 75(Suppl 2): 175.1-175, 2016

THU0093Deiminated Histone 4 from Neutrophil Extracellular Traps is a Novel Autontigen in Rheumatoid Arthritis. Annals of the Rheumatic Diseases 72(Suppl 3): A194.2-A194, 2013

Enhanced release of neutrophil extracellular traps from peripheral blood neutrophils in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 71(Suppl 1): A79.2-A79, 2012

Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation. European Journal of Immunology 46(11): 2542-2554, 2016

Caught in a Trap? Proteomic Analysis of Neutrophil Extracellular Traps in Rheumatoid Arthritis and Systemic Lupus Erythematosus. Frontiers in Immunology 10: 423, 2019

IgA Complexes in Plasma and Synovial Fluid of Patients with Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI. Journal of Immunology 197(12): 4552-4559, 2017

1,25(OH) 2 D 3 and calcipotriol, its hypocalcemic analog, exert a long-lasting anti-inflammatory and anti-proliferative effect in synoviocytes cultured from patients with rheumatoid arthritis and osteoarthritis. Journal of Steroid Biochemistry and Molecular Biology 173: 13-22, 2017

Neutrophil Extracellular Traps Reprogram IL-4/GM-CSF-Induced Monocyte Differentiation to Anti-inflammatory Macrophages. Frontiers in Immunology 8: 523, 2017

Circulating levels of carbamylated protein and neutrophil extracellular traps are associated with periodontitis severity in patients with rheumatoid arthritis: A pilot case-control study. Plos One 13(2): E0192365, 2018

Neutrophil Extracellular Traps Exert Potential Cytotoxic and Proinflammatory Effects in the Dental Pulp. Journal of Endodontics 2019, 2019

A6.43 Neutrophil extracellular traps are not only targets for Acpa but also directly trigger pro- and anti-inflammatory effects partly mediated by the C1Q complement protein. Annals of the Rheumatic Diseases 74(Suppl 1): A73-A74, 2015

Selenium Nanoparticles Dispersed in Phytochemical Exert Anti-Inflammatory Activity by Modulating Catalase, GPx1, and COX-2 Gene Expression in a Rheumatoid Arthritis Rat Model. Medical Science Monitor 25: 991-1000, 2019