Redirecting TGF-β Signaling through the β-Catenin/Foxo Complex Prevents Kidney Fibrosis

Abstract

TGF-<i>β</i> is a key profibrotic factor, but targeting TGF-<i>β</i> to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-<i>β</i> signaling by preventing downstream profibrotic interaction of <i>β</i>-catenin with T cell factor (TCF), thereby enhancing the interaction of <i>β</i>-catenin with Foxo, a transcription factor that controls differentiation of TGF-<i>β</i> induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-<i>β</i> In iTregs derived from EL4 T cells treated with recombinant human TGF-<i>β</i>1 (rhTGF-<i>β</i>1) <i>in vitro</i>, inhibition of <i>β</i>-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of <i>β</i>-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of <i>β</i>-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3^gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-<i>β</i>1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-<i>β</i>1 treatment alone. Coadministration of rhTGF-<i>β</i>1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-<i>β</i>1. Together, our results show that diversion of <i>β</i>-catenin from TCF- to Foxo-mediated transcription inhibits the <i>β</i>-catenin/TCF-mediated profibrotic effects of TGF-<i>β</i> while enhancing the <i>β</i>-catenin/Foxo-mediated anti-inflammatory effects. Targeting <i>β</i>-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.