SAA1/TLR2 Axis Directs Chemotactic Migration of Hepatic Stellate Cells Responding to Injury

Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, by using CCl4- and cryoinjury-induced acute liver injury models in C57/BL6 mice, we demonstrate that the injury-induced and hepatocytes secreted an acute phase protein, serum amyloid A (SAA) is a chemokine attracting HSCs into injury loci. The mRNA-based screening and antagonist administration indicated that the toll-like receptor 2 (TLR2) was a chemotactic receptor on HSCs responding to SAA, and further confirmed by TLR2 knockout HSC cell line LX-2 in vitro and in vivo models. On other hand, genetic depletion of SAA in mice impaired the recruitment of HSCs into injured loci. Moreover, SAA/TLR2 axis appeared to be actively involved in the homing of intrasplenically transplanted LX-2 cells in both CCl4- and cryo-injured livers of NOD-SCID-IL2RG−/− mice. The mechanistic study revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K dependent pathway and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and inhibition of PI3K or Rac GTPase diminished the phosphorylation of MLCpSer19 and chemotactic migration. The evidence concluded that the injury induced chemotactic migration of HSCs is directed by SAA1 which serving as a hepatic endogenous chemokine, and the chemotactic receptor on HSCs is TLR2; the SAA1/TLR2 binding initiates PI3K dependent signaling and its effector, Rac GTPases that dynamically regulates actin filaments remodeling and cell directional migration. Our finding provides novel targets for anti-fibrosis drug development.