A macrophage-smooth muscle cell axis influences vascular remodeling through activation of the EGFR pathway in giant cell arteritis

Background. The role of macrophages and vascular resident cells appears to be predominant in the pathophysiology of giant cell arteritis (GCA). We investigated the role of epithelial growth factor receptor (EGFR) signaling pathway, especially through its activation by heparin-binding epidermal growth factor (HB-EGF) and/or amphiregulin (AREG) in this setting. Materials and Methods. Serum samples and temporal artery biopsies (TAB) were obtained from patients enrolled in a prospective cohort of systemic vasculitis. Human THP-1, a monocytic cell line, and human aortic vascular smooth muscle cells (VSMC) were used for in vitro studies. Results. Using multiplex immunohistochemistry, TAB from GCA patients showed higher expression of AREG, HB-EGF, EGFR and phospho-EGFR as compared to control arteries. AREG, HB-EGF and EGFR were predominantly expressed by macrophages, whereas EGFR and phosphor-EGFR were expressed by αSMA-positive cells in the media. Increased levels of AREG and HB-EGF were found in culture supernatants of M1 macrophages, whereas M2 macrophages produced only HB-EFG. AREG and HB-EGF did not increase the production of pro-inflammatory cytokines by THP-1 or macrophages but activated the p38 MAPK pathway. Using transcriptomic and Western blot analysis of human aortic VSMC, AREG and especially HB-EGF induced cell proliferation pathway, enhanced interferon alpha and gamma responses, and activation of the MAPK pathway. Finally, AREG and HB-EGF increased both VSMC proliferation and migration, which were completely inhibited by AG1478, an EGFR inhibitor. Conclusion. We show that both AREG and HB-EGF may play a role in the pathophysiology of GCA, especially in the remodeling phase of the disease.