Targeting thrombospondin-2 retards liver fibrosis by inhibiting TLR4-FAK/TGF-β signaling
Ning Zhang, Xiaoning Wu, Wen Zhang, Yameng Sun, Xuzhen Yan, Anjian Xu, Qi Han, Aiting Yang, Hong You, Wei Chen
Abstract
Background & Aims: Thrombospondin-2 (THBS2) expression is associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has yet to be elucidated. Methods: , under the regulatory control of cytomegalovirus, U6 or the α-smooth muscle promoter, in mouse models of carbon tetrachloride or methionine-choline deficient (MCD) diet-induced liver fibrosis. Crosstalk between THBS2 and toll-like receptor 4 (TLR4), as well as the cascaded signaling, was systematically investigated using mouse models, primary HSCs, and human HSC cell lines. Results: in HSCs retarded intrahepatic inflammatory infiltration, steatosis accumulation, and fibrosis progression following carbon tetrachloride challenge or in a dietary model of metabolic dysfunction-associated steatohepatitis. Mechanically, extracellular THBS2, as a dimer, specifically recognized and directly bound to TLR4, activating HSCs by stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-β) pathways. Disruption of the THBS2-TLR4-FAK/TGF-β signaling axis notably alleviated HSC activation and liver fibrosis aggravation. Conclusions: THBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-β signaling in an autocrine manner, representing an attractive potential therapeutic target for liver fibrosis. Impact and implications: Thrombospondin-2 (THBS2) is emerging as a factor closely associated with liver fibrosis regardless of etiology. However, the mechanisms by which THBS2 is involved in liver fibrosis remain unclear. Here, we showed that THBS2 plays a prominent role in the pathogenesis of liver fibrosis by activating the TLR4-TGF-β/FAK signaling axis and hepatic stellate cells in an autocrine manner, providing a potential therapeutic target for the treatment of liver fibrosis.