The effect of core fucosylation-mediated regulation of multiple signaling pathways on lung pericyte activation and fibrosis

Abstract

The main event in the progression of pulmonary fibrosis is the appearance of myofibroblasts. Recent evidence supports pericytes as a major source of myofibroblasts. TGFβ/Smad2/3 and PDGF/Erk signaling pathways are important for regulating pericyte activation. Previous studies have demonstrated that PDGFβR and TGFβR are modified by core fucosylation (CF) catalyzed by α-1,6-fucosyltransferase (FUT8). The aim of this study was to compare the effect of inhibiting CF versus the PDGFβR and TGFβR signaling pathways on pericyte activation and lung fibrosis. FUT8shRNA was used to knock down FUT8-mediated CF both in vivo and in isolated lung pericytes. The small molecule receptor antagonists, ST1571 (imatinib) and LY2109761, were used to block the PDGFβ/pErk and TGFβ/pSmad2/3 signaling pathways, respectively. Pericyte detachment and myofibroblastic transformation were assessed by immunofluorescence and Western blot. Histochemical and immunohistochemical staining were used to evaluate the effect of the intervention on pulmonary fibrosis. Our findings demonstrate that FUT8shRNA significantly blocked pericyte activation and the progression of pulmonary fibrosis, achieving intervention effects superior to the small molecule inhibitors. The PDGFβ and TGFβ pathways were simultaneously affected by the CF blockade. FUT8 expression was upregulated with the transformation of pericytes into myofibroblasts, and silencing FUT8 expression inhibited this transformation. In addition, there is a causal relationship between CF modification catalyzed by FUT8 and pulmonary fibrosis. Our findings suggest that FUT8 may be a novel therapeutic target for pulmonary fibrosis.

Keywords: FUT8; Myofibroblasts; Pericytes; Pulmonary fibrosis.