MicroRNA-29a mitigation of toll-like receptor 2 and 4 signaling and alleviation of obstructive jaundice-induced fibrosis in mice.

ABSTRACT

Cholestasis and hepatitis can cause continuous liver damage that may ultimately result in liver fibrosis. In a previous study, we demonstrated that microRNA-29a (miR-29a) protects against liver fibrosis. Toll-like receptor 2 (TLR2) and TLR4 are pattern recognition receptors of bacterial lipoprotein and lipopolysaccharide, both of which participate in activating hepatic stellate cells and liver fibrosis. The purpose of this study is to characterize the biological influence of miR-29a on TLR2 and TLR4 signaling in livers injured with bile duct ligation (BDL). We performed BDL on both miR-29a transgenic mice (miR-29aTg) and wild-type mice to induce cholestatic liver injury. Primary HSCs were transfected with a miR-29a mimic and inhibitor. In the wild-type mice, the BDL demonstrated significant α-smooth muscle actin fibrotic matrix formation and hepatic high mobility group box-1 expression. However, in the miR-29aTg mice, these factors were significantly reduced. Furthermore, miR-29a overexpression reduced the BDL exaggeration of TLR2, TLR4, MyD88, bromodomain-containing protein 4 (BRD4), phospho-p65 as well as proinflammatory cytokines, IL-1ß, MCP-1, TGF-ß, and TNF-α. In vitro, miR-29a mimic transfection reduced α-SMA, BRD4,TLR2, and TLR4 expressions in HSCs. This study provides new molecular insight into the ability of miR-29a to inhibit TLR2 and TLR4 signaling, which thus slows the progression of cholestatic liver deterioration.