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Regulation of Inflammation and Angiogenesis in Giant Cell Arteritis by Acute‐Phase Serum Amyloid A
Author(s) -
O'Neill Lorraine,
Rooney Peadar,
Molloy Danielle,
Connolly Mary,
McCormick Jennifer,
McCarthy Geraldine,
Veale Douglas J.,
Murphy Conor C.,
Fearon Ursula,
Molloy Eamonn
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39217
Subject(s) - matrigel , angiogenesis , proinflammatory cytokine , serum amyloid a , pathology , neovascularization , inflammation , giant cell arteritis , immunology , biology , medicine , vasculitis , disease
Objective Giant cell arteritis (GCA) is pathologically characterized by dysfunctional angiogenesis and inflammatory cell infiltration. Acute‐phase serum amyloid A (A‐SAA) is an acute‐phase reactant, but is also produced at sites of inflammation and may contribute to vascular inflammation in atherosclerosis. This study was undertaken to examine the effect of A‐SAA on proinflammatory pathways and angiogenesis in GCA, using a novel ex vivo temporal artery tissue explant model. Methods Serum A‐SAA levels were measured by enzyme‐linked immunosorbent assay (ELISA). Temporal artery explants and peripheral blood mononuclear cell (PBMC) cultures were established from patients with GCA. Temporal artery explant morphology, viability, and spontaneous release of proinflammatory mediators following 24‐hour culture were assessed by hematoxylin and eosin, calcein viability staining, and ELISA. Temporal artery explants and PBMC cultures were stimulated with A‐SAA (10 μg/ml), and interleukin‐6 (IL‐6), IL‐8, vascular endothelial growth factor, Ang2, and matrix metalloproteinase 2 (MMP‐2)/MMP‐9 were quantified by ELISA and gelatin zymography. The effect of conditioned medium from temporal artery explants on angiogenesis was assessed using endothelial cell Matrigel tube‐formation assays. Temporal artery explants were also embedded in Matrigel, and myofibroblast outgrowth was assessed. Results Serum A‐SAA levels were significantly higher in GCA patients versus healthy controls ( P < 0.0001). Intact tissue morphology, cell viability, and spontaneous cytokine secretion were demonstrated in temporal artery explants. A‐SAA treatment induced a significant increase in the levels of IL‐6 and IL‐8 from temporal artery explants ( P < 0.05) and IL‐8 from PBMCs ( P < 0.05) compared to basal conditions. Conditioned medium from A‐SAA–treated explants significantly induced angiogenic tube formation ( P < 0.05 versus basal controls). Finally, A‐SAA induced myofibroblast outgrowth and MMP‐9 activation. Conclusion Our findings demonstrate a functional role for A‐SAA in regulating temporal artery inflammation, angiogenesis, and invasion, all key processes in the pathogenesis of GCA.