Objectives: Takayasu's arteritis (TAK) is characterised by inflammation and fibrosis in the aortas, but its pathogenesis remains unclear. The aim of the study is to demonstrate the role of cysteine-rich protein 61 (CYR61), a novel proinflammatory factor, in the inflammation and fibrosis of TAK vessels.
Methods: CYR61 expression in the aortic vessel was compared between TA tissues and healthy samples by immunohistochemistry staining. The effect of CYR61 on the proliferation, migration and activation of adventitial fibroblasts (AFs) in the IL-17-mediated inflammatory microenvironment was studied in vitro.
Results: Here we found higher expression of CYR61 in the aortic adventitia in TAK patients than in healthy donors by immunohistochemistry staining. In vitro, recombinant human CYR61 (rhCYR61) significantly upregulated the proliferation of primary human aortic adventitial fibroblasts (AFs) and their expression of extracellular matrix (ECM) proteins such as collagen I, collagen III and fibronectin at the mRNA and protein levels, but rhCYR61 partly inhibited the migration of AFs. The integrin αvβ1 was identified as a membrane receptor of CYR61 in AFs, and its downstream Erk1/2 pathway was found activated by detecting its phosphorylation level. Pretreatment with PD98059, an inhibitor of Erk1/2, down-regulated the mRNA and protein expression of ECM proteins in the rhCYR61-stimulated AFs. Furthermore, rhCYR61 up-regulated the expression of TGF-β, and TGF-β siRNA transfection obviously attenuated the profibrotic effect ofrhCYR61. Finally, to clarify the cooperation between CYR61 and classical proinflammatory factors, IL-17 was chosen as a co-stimulator in the culture of AFs. rhIL-17 promoted the mRNA and protein expression of CYR61 in AFs, and the collaboration of rhIL-17 and rhCYR61 dramatically boosted the synthesis of ECM and TGF-β.
Conclusions: Our findings suggest that CYR61 played a profibrotic role through the TGF-β pathway and it enhanced IL-17-mediated inflammation and fibrosis in the mechanism of vascular impairment in TAK.