TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.
