TGF‐β‐induced profibrotic signaling is regulated in part by the WNT receptor Frizzled‐8

TGF‐β is important in lung injury and remodeling processes. TGF‐β and Wingless/integrase‐1 (WNT) signaling are interconnected; however, the WNT ligand‐receptor complexes involved are unknown. Thus, we aimed to identify Frizzled (FZD) receptors that mediate TGF‐β‐induced profibrotic signaling. MRC‐5 and primary human lung fibroblasts were stimulated with TGF‐β1, WNT‐5A, or WNT‐5B in the presence and absence of specific pathway inhibitors. Specific small interfering RNA was used to knock down FZD8. In vivo studies using bleomycin‐induced lung fibrosis were performed in wild‐type and FZD8‐deficient mice. TGF‐β 1 induced FZD8 specifically via Smad3‐dependent signaling in MRC‐5 and primary human lung fibroblasts. It is noteworthy that FZD8 knockdown reduced TGF‐β1‐induced collagen Iα1, fibronectin, versican, α‐smooth muscle (sm)‐actin, and connective tissue growth factor. Moreover, bleomycin‐induced lung fibrosis was attenuated in FZD8‐deficient mice in vivo. Although inhibition of canonical WNT signaling did not affect TGF‐β 1‐induced gene expression in vitro, noncanonical WNT‐5B mimicked TGF‐β1‐induced fibroblast activation. FZD8 knockdown reduced both WNT‐5B‐induced gene expression of fibronectin and α‐sm‐actin, as well as WNT‐5B‐induced changes in cellular impedance. Collectively, our findings demonstrate a role for FZD8 in TGF‐β‐induced profibrotic signaling and imply that WNT‐5B may be the ligand for FZD8 in these responses.—Spanjer, A. I. R., Baarsma, H. A., Oostenbrink, L. M., Jansen, S. R., Kuipers, C. C., Lindner, M., Postma, D. S., Meurs, H., Heijink, I. H., Gosens, R., Königshoff, M. TGF‐β‐induced profibrotic signaling is regulated in part by the WNT receptor Frizzled‐8. FASEB J. 30, 1823–1835 (2016). www.fasebj.org