Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis

Yeo, Lorraine; Adlard, Nichola Jayne; Biehl, Michael; Juárez, Maria; Smallie, Tim; Snow, Martyn; Buckley, Christopher D.; Raza, Karim; Filer, Andrew; Scheel‐Toellner, Dagmar

doi:10.1136/annrheumdis-2014-206921

Cited by 119 publications

(102 citation statements)

References 39 publications

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“…98 Synovial biopsy may be useful, as a diagnostic and prognostic tool, for the differential diagnosis in early inflammatory arthritis in whom synovial CD22 and CD38 expression may distinguish between RA and non-RA disease. 99 The value of synovial biopsy markers as selected diagnostic and prognostic markers to establish an early diagnosis is clearly still evolving.…”

Section: Early Arthritis and Early Diagnosismentioning

confidence: 99%

“…102,103 This is the so-called 'tailor-made' treatment, informed by biomarkers, used to assess what has been referred to as 'disease signatures'. 98 A more accurate description of this process is disease 'stratification'. 104,105 This concept proposes that a disease can be stratified into distinct subsets that exhibit differential outcomes and responses, each subset labelled by a biomarker or combination thereof.…”

Section: 'Personalised Medicine' and Disease Stratificationmentioning

confidence: 99%

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Synovial tissue research: a state-of-the-art review

et al. 2017

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The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis (RA). The study of synovial tissue has advanced significantly over a number of decades from arthroplasty, blind needle biopsy and more recently facilitated by arthroscopic and ultrasonographic technology that allows easier visualisation and improves the reliability of obtaining synovial biopsies. The potential for study of pathogenesis, patient stratification, discovery of biomarkers and novel targets, as well as validation of therapy, have all been progressed rapidly in the last decade, facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this review we describe clinical and translational developments in the field of synovial tissue research, outlining current and novel investigative technologies, and highlight their application to advance our understanding of the aforegoing imperatives.3

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Section: Early Arthritis and Early Diagnosismentioning

confidence: 99%

Section: 'Personalised Medicine' and Disease Stratificationmentioning

confidence: 99%

Synovial tissue research: a state-of-the-art review

et al. 2017

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“…CXCL7 plays a critical role in recruiting neutrophils to a variety of tissues, and dysregulation in this process has been implicated in inflammatory diseases, such as rheumatoid arthritis, acute lung injury and COPD [50,51,52], as well as a variety of cancers [53,54]. One of its primary functions involves neutrophil-platelet crosstalk during vascular injury, as it is released at relatively high concentrations from activated platelets and provides cues for directed neutrophil migration to the injury site [7].…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Brown

Sepuru

Rajarathnam

2017

IJMS

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CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family.

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“…Synovial tissue was obtained from patients with established RA and healthy individuals by ultrasound-guided synovial biopsy as previously described [14]. Cartilage tissue was obtained from healthy areas of cartilage in patients undergoing joint replacement surgery for osteoarthritis.…”

Section: Methodsmentioning

confidence: 99%

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

et al. 2016

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BackgroundWe investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.MethodsSynovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined. To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.ResultsSF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells. TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF-β1 induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage. PDPN+ CD248– SF preceded the appearance of PDPN– CD248+ cells in contralateral implants.ConclusionsWe have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane. These markers discriminate between SF subsets with distinct biological properties. As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.

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Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis

Cited by 119 publications

References 39 publications

Synovial tissue research: a state-of-the-art review

Synovial tissue research: a state-of-the-art review

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

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