CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-?/Smad signaling

Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prog-nosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-beta/Smad signaling pathway to pro-mote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.

Automated summary

Pulmonary fibrosis (PF) is a fatal respiratory disease with limited treatment options. The chemokine CCL17 plays a crucial role in the development of immune diseases, and its levels are elevated in PF patients. In this study, it was found that CCL17 is upregulated in the lungs of PF patients and mice with induced PF. The interaction between CCL17 and its receptor CCR4 activates the TGF-beta/Smad signaling pathway, promoting fibroblast activation and tissue fibrosis. Blocking CCL17 or CCR4 can inhibit fibroblast activation and tissue fibrosis, potentially benefiting patients with fibroproliferative lung diseases.