Increased expression of Toll-like receptors and associated alarmins in temporal arteries of patients with giant cell arteritis

Abstract

Background: Giant cell arteritis (GCA) is a chronic granulomatous inflammatory disease involving large- and medium-sized arteries. The disease spectrum comprises cranial (C-GCA), extracranial (EC-GCA) and mixed phenotypes. Toll-like receptors (TLRs) in the affected arteries may play an important role in GCA pathogenesis. However, data on TLR and TLR-ligands expression pattern in GCA arteries are lacking. Objective: To investigate the expression of TLRs and putative ligands in temporal artery biopsies (TAB) from C-GCA, EC-GCA and isolated polymyalgia rheumatica (PMR) patients to establish a link between TLRs, antigen expression, and disease stage. To correlate the plasma levels of identified TLR-ligands with standard inflammatory markers (IL-6, CRP, ESR) in these patients. Methods: Immunofluorescence staining of TLR2/4/7/8, HMGB-1, SAA, fibrinogen, and p-glycoprotein was performed with TABs of six biopsy proven C-GCA, six EC-GCA, five PMR patients and seven age-matched controls. Association studies among plasma inflammatory markers were done with 139 PMR and 40 GCA patients. Results: The levels of TLR2/4/7/8 and the alarmins HMGB-1, SAA, and fibrinogen were highly increased in C-GCA TABs in the sites of inflammation and less in EC-GCA TABs. P-glycoprotein was overexpressed in C-GCA TABs. Glucocorticoids or TAK1-inhibitor treatment decreased the fibrinogen- and SAA-mediated IL-6 production in control PBMCs. Plasma levels of SAA and fibrinogen associated strongly with CRP and ESR levels. Conclusion: TLRs are overexpressed at the site of vascular inflammation in C-GCA and at a lower level in EC-GCA and PMR with negative TAB. Moreover, HMGB-1, SAA, and fibrinogen may serve as disease biomarkers of patients with C-GCA.