The Role And Mechanism Of Wnts Signaling Pathway In Regulating Macrophage Activation And Tubulointerstitial Fibrosis

The Wnt/?-catenin pathway is crucial in normal development and throughout life,but aberrant activation of this pathway has been linked to kidney fibrosis,although the mechanisms involved remain incompletely determined.Here,we investigated the role of Wnt/?-catenin in regulating macrophage activation and the contribution thereof to kidney fibrosis.Treatment of macrophages with Wnt3a exacerbated IL-4-or TGF?1-induced macrophage alternative(M2)polarization and the phosphorylation and nuclear translocation of STAT3 in vitro.Conversely,inhibition of Wnt/?-catenin signaling prevented these IL-4-or TGF?1-induced processes.Treatment of BMMs with Stattic,an STAT3 inhibitor could largely inhibit STAT3 phosphorylation and macrophage M2 polarization induced by IL-4 or TGF?1 plus Wnt3a.In a mouse model,induced deletion of ?-catenin in macrophages attenuated the fibrosis,macrophage accumulation and M2 polarization observed in the kidneys of wild-type littermates after unilateral ureter obstruction.This study shows that activation of Wnt/?-catenin signaling promotes kidney fibrosis by stimulating macrophage M2 polarization.The Wnt5a is implicated in the noncanonical Wnt signaling and plays a pivotal role in controlling embryonic and fetal development and post-natal homeostasis.Dysregulation of Wnt5a signaling is associated with myriad pathologies,including inflammation,fibrosis and cancer.However,little is known about the role of Wnt5a in regulating macrophage activation and kidney fibrosis.Here we found that treatment of macrophages with Wnt5a up-regulated the activation of YAP/TAZ and promoted TGFpi-induced macrophage M2 polarization in vitro.These effects were blocked by inhibition of YAP with Verteporfin.Additionally,up-regulation of exogenous TAZ in macrophage through transfecting with 3XFlag pCMV5-TOPO TAZ promoted macrophage M2 plorization.In a mouse model,Wnt5a expression was increased in fibrotic kidney after unilateral ureter obstruction(UUO)or ischemia-reperfusion injury(IRI).ShRNA-mediated knockdown of Wnt5a in liver and kidney diminished fibrosis,macrophage accumulation and M2 polarization and down-regulated the activation of YAP/TAZ in macrophages showed in kidneys after UUO or IRI.Conversely,expression of exogenous Wnt5a through tail vein injection with pcDNA-Wnt5a aggravated fibrosis,macrophage M2 polarization and up-regulated of YAP/TAZ expression observed in kidneys after UUO or IRI.In a mouse model,induced deletion of TAZ in macrophages attenuated the fibrosis,macrophage accumulation and M2 polarization observed in the kidneys of wild-type littermates after unilateral ureter obstruction.Collectively,we suggest that Wnt5a promotes TGFpi-induced macrophage M2 polarization by up-regulating the activation of YAP/TAZ and contribution thereof to kidney fibrosis.