YKL-40 Promotes Chemokine Expression Aggravating Drug-Induced Liver Injury Via TF-PAR1 Pathway In Mice

Objectives:Drug induced liver injury（drug-induced liver injury,DILI）is one of the important causes of acute liver failure and liver transplantation.In recent years,the incidence rate has increased year by year,which has aroused widespread concern.Research has found an important connection between the onset of liver diseases and inflammation.The inflammatory factor YKL-40（Chitinase-3-like protein 1,Chi3l1）has been proven to be associated with various inflammatory diseases and plays an important role in the remodeling process of inflammatory cells and tissue structure in the body.More and more Blood studies have shown that intrahepatic vascular coagulation（IAOC）is an important cause of liver fibrosis,cirrhosis,and liver cancer development^[2-4].YKL-40,as a derivative of chitinase,is widely present in various mammalian vertebrate cells,and its overexpression is involved in the pathogenesis and prognosis of a series of inflammatory response diseases.YKL-40 can affect angiogenesis activity,inflammatory microenvironment,epithelial mesenchymal transformation and other processes by promoting the release of related inflammatory factors,activating corresponding signal transduction pathways,thus affecting the occurrence and development of diseases.In a mouse model of acute hepatitis induced by concanavalin A（ConA）,it has been demonstrated that YKL-40 promotes the activation of tissue factor（TF）,which in turn induces intrahepatic vascular coagulation（IAOC）and ultimately leads to liver injury.Liver diseases are closely related to TF,which is not only a key promoter of the exogenous coagulation cascade cascade cascade,but also participates in many signaling pathways,thereby affecting cell proliferation,apoptosis,pyroptosis,migration,and the pathogenesis of inflammatory diseases.The abnormal expression of chemokines is closely related to the progression of hepatitis diseases and plays an important role in the pathophysiology of immune hepatitis,the development of liver inflammation,and subsequent wound healing reactions.Research has shown that when inflammatory diseases occur,TF can promote the progression of inflammatory diseases,cancer,and other diseases by activating protease activated receptors（PARS）.It is worth noting that TF affects cell proliferation,apoptosis,migration,and recruitment of inflammatory cells through the TF-PAR1 pathway.Given its unique role,exploring the expression of downstream chemokine ligand 2（CCL2）and chemokine IP-10（Iterferon inducible protein-10）in the TF-PAR1 pathway activated by YKL-40 can help to better investigate the pathogenesis of drug-induced liver injury,and use targeted therapy to intervene in the disease’s course in the early stage,providing a new treatment plan for its clinical treatment.Methods:1.The liver injury model of C57BL/6 mice was established by ConA.2.Use enzyme-linked immunosorbent assay（ELISA）and hematoxylin-eosin staining（HE staining）to determine the relationship between the expression of YKL-40 and the severity of the disease.3.The expression of TF,PAR1,CCL2 and IP-10 was measured by Western blot,real-time fluorescent quantitative PCR（qRT-PCR）,immunohistochemistry staining（IHC）and other experimental techniques,so as to clarify the effect of TF-PAR1 pathway induced by YKL-40 on the expression level of its downstream chemokine CCL2 and IP-10.Results:1.Compared with wild-type and model group mice,as the expression level of YKL-40 increases,liver tissue congestion worsens,cell edema is obvious,and punctate or flaky necrosis begins to appear.The degree of damage shows a significant worsening trend.2.YKL-40 promotes the expression of downstream chemokine CCL2 and IP-10 by inducing TF-PAR1 pathway,thus exacerbating the progression of DILI induced by ConA.3.When the TF-PAR1 pathway induced by YKL-40 is blocked,the expression level of its downstream chemokine CCL2 and IP-10 decreases,which effectively alleviates the progression of DILI induced by ConA.Conclusions:Our data reveal the proinflammatory pathogenesis of TF-PAR1 pathway induced by YKL-40.YKL-40 can promote the expression of chemokine CCL2 and IP-10by inducing liver TF-PAR1 pathway,leading to increased recruitment of inflammatory cells and aggravating the progression of liver injury.This provides a new target for the clinical treatment of drug-induced liver injury.