Interferon-λ drives renal fibrosis by coordinating epithelial-fibroblast crosstalk

Renal fibrosis is a critical step in chronic kidney disease (CKD) progression, but fibrosis induction is still not understood well. We found that IFN-λ is a profibrotic factor that is upregulated in fibrotic human and mouse kidneys. IFN-λ receptor deficiency ameliorated renal fibrosis in mice while exogenous IFN-λ exacerbated disease, establishing a detrimental role of IFN-λ signaling in renal fibrosis. Mechanistically, we found that IFN-λ promotes fibrosis by preferentially acting on renal fibroblasts, inducing their activation and migration through ERK/JNK-dependent synthesis of TGF-β and activation of the TGF-β-SMAD2/3 signaling pathway. Renal tubular epithelial cell (TEC)-derived IFN-λ induced by RIG-I/MAVS signaling emerged as a critical driver of renal fibroblast activation and fibrogenesis. Importantly, neutralizing antibodies against IFN-λ strongly attenuated renal fibrosis in mice. Thus, the renal TEC-IFN-λ-fibroblast axis is a previously unrecognized pathway of renal fibrosis induction that represents an attractive novel target for mitigating CKD progression.