Proteomic analysis of synovial fluid from rheumatic arthritis and spondyloarthritis patients

Birkelund, Svend; Bennike, Tue Bjerg; Kastaniegaard, Kenneth; Lausen, Mads; Poulsen, Thomas B.; Kragstrup, Tue Wenzel; Christiansen, Gunna; Stensballe, Allan

doi:10.1186/s12014-020-09292-9

Cited by 29 publications

(37 citation statements)

References 57 publications

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“…Recent proteomic analysis of SF from RA patients and spondyloarthritis (SpA) patients identified elevated levels of many neutrophil proteins in RA SF, including MPO, cathepsin G, annexin-A1 and NGAL. Interestingly, whilst the concentration of cell-free DNA did not differ between RA and SpA SF, the levels of 21 NET proteins were elevated in RA SF, including histones H2A, H2B and H4, MMP9, elastase, and a-enolase (12). It has previously been shown that levels of ACPA in RA SF correlate with neutrophil numbers and severe disease activity, and that SFs with high ACPA titers induce high levels of ROS and NET production (70).…”

Section: Discussionmentioning

confidence: 95%

“…As well as having an activated phenotype in peripheral blood, activated neutrophils are found at high numbers in both synovial joints and tissues of patients with RA (5)(6)(7). Their presence within RA joints is accompanied by high levels of neutrophil granule proteins in synovial fluid, including myeloperoxidase (MPO), cathepsin G, proteinase 3, elastase, and lactoferrin (1,(8)(9)(10)(11)(12). These granule proteins contribute to the pathogenesis of RA through proteolytic cleavage and activation of proteins (including cytokines and chemokines), cleavage of soluble receptors to initiate transsignaling (such as the IL-6 receptor) and degradation of cartilage (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Rheumatoid Arthritis Synovial Fluid Neutrophils Drive Inflammation Through Production of Chemokines, Reactive Oxygen Species, and Neutrophil Extracellular Traps

et al. 2021

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Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting synovial joints. Neutrophils are believed to play an important role in both the initiation and progression of RA, and large numbers of activated neutrophils are found within both synovial fluid (SF) and synovial tissue from RA joints. In this study we analyzed paired blood and SF neutrophils from patients with severe, active RA (DAS28>5.1, n=3) using RNA-seq. 772 genes were significantly different between blood and SF neutrophils. IPA analysis predicted that SF neutrophils had increased expression of chemokines and ROS production, delayed apoptosis, and activation of signaling cascades regulating the production of NETs. This activated phenotype was confirmed experimentally by incubating healthy control neutrophils in cell-free RA SF, which was able to delay apoptosis and induce ROS production in both unprimed and TNFα primed neutrophils (p<0.05). RA SF significantly increased neutrophil migration through 3μM transwell chambers (p<0.05) and also increased production of NETs by healthy control neutrophils (p<0.001), including exposure of myeloperoxidase (MPO) and citrullinated histone-H3-positive DNA NETs. IPA analysis predicted NET production was mediated by signaling networks including AKT, RAF1, SRC, and NF-κB. Our results expand the understanding of the molecular changes that take place in the neutrophil transcriptome during migration into inflamed joints in RA, and the altered phenotype in RA SF neutrophils. Specifically, RA SF neutrophils lose their migratory properties, residing within the joint to generate signals that promote joint damage, as well as inflammation via recruitment and activation of both innate and adaptive immune cells. We propose that this activated SF neutrophil phenotype contributes to the chronic inflammation and progressive damage to cartilage and bone observed in patients with RA.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Rheumatoid Arthritis Synovial Fluid Neutrophils Drive Inflammation Through Production of Chemokines, Reactive Oxygen Species, and Neutrophil Extracellular Traps

et al. 2021

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“…ROS production within RA blood leads to modifications of immunoglobulin G (IgG) which are associated with increased immunogenicity and production of rheumatoid factor immune complexes ( 93 ). Within the RA joint IgG complexes, both soluble and embedded within synovial tissue, activate further ROS production by neutrophils via activation of FcγR2a and FcγR3b ( Figure 2 ) ( 94 , 95 ), and trigger degranulation of proteolytic enzymes including elastase and cathepsin G ( 8 , 26 , 56 , 96 – 98 ). When this occurs at the articular surface a microenvironment of concentrated ROS, proteases and cytotoxic factors is formed, damaging the underlying structures ( 8 ).…”

Section: Ros Mediated Tissue Damagementioning

confidence: 99%

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

2021

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Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins. Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE). Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies. An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE. Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease. In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition. We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease.

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“…Leon et al analyzed the DNA levels in paired samples of serum and synovial fluid from patients with arthritis, including some samples from patients with psoriatic arthropathy and AS, but no clear results were found [ 63 ]. Recently, Birkelund et al reported that the presence of cfDNA correlates with proteins predominantly found in neutrophil granulocytes in synovial fluid from SpA patients [ 77 ]. Further studies involving larger numbers of SpA patients are needed to investigate the role of cfDNA in these kinds of diseases.…”

Section: Circulating Free Dna In Autoimmune Rheumatic Diseasesmentioning

confidence: 99%

Circulating Free DNA and Its Emerging Role in Autoimmune Diseases

Mondelo‐Macía

Castro‐Santos

Castillo‐García³

et al. 2021

JPM

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Liquid biopsies can be used to analyse tissue-derived information, including cell-free DNA (cfDNA), circulating rare cells, and circulating extracellular vesicles in the blood or other bodily fluids, representing a new way to guide therapeutic decisions in cancer. Among the new challenges of liquid biopsy, we found clinical application in nontumour pathologies, including autoimmune diseases. Since the discovery of the presence of high levels of cfDNA in patients with systemic lupus erythaematosus (SLE) in the 1960s, cfDNA research in autoimmune diseases has mainly focused on the overall quantification of cfDNA and its association with disease activity. However, with technological advancements and the increasing understanding of the role of DNA sensing receptors in inflammation and autoimmunity, interest in cfDNA and autoimmune diseases has not expanded until recently. In this review, we provide an overview of the basic biology of cfDNA in the context of autoimmune diseases as a biomarker of disease activity, progression, and prediction of the treatment response. We discuss and integrate available information about these important aspects.

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Proteomic analysis of synovial fluid from rheumatic arthritis and spondyloarthritis patients

Cited by 29 publications

References 57 publications

Rheumatoid Arthritis Synovial Fluid Neutrophils Drive Inflammation Through Production of Chemokines, Reactive Oxygen Species, and Neutrophil Extracellular Traps

Rheumatoid Arthritis Synovial Fluid Neutrophils Drive Inflammation Through Production of Chemokines, Reactive Oxygen Species, and Neutrophil Extracellular Traps

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

Circulating Free DNA and Its Emerging Role in Autoimmune Diseases

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