Zhao Shan1, Xiaodong Liu2, Yuan Chen1, Meng Wang1, Yue Rachel Gao1, Liangguo Xu1, Wasim A Dar3, Chun Geun Lee4, Jack Angel Elias4,5, Pavel Davizon Castillo6, Jorge Di Paola6, Cynthia Ju1,7. 1. Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA. 2. Department of Pharmacy, Sheng-jing Hospital of China Medical University, Shengyang, Liaoning, P.R. China. 3. Department of Surgery, UTHealth McGovern Medical School, Houston, TX, USA. 4. Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, New Haven, CT, USA. 5. Division of Medicine and Biological Sciences, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, New Haven, CT, USA. 6. Department of Pediatric, School of Medicine, University of Colorado Denver, Aurora, CO, USA. 7. Integrated Department of Immunology, University of Colorado Denver Aurora, CO, USA.
Abstract
Coagulation is a critical component in the progression of liver disease. Identification of key molecules involved in the intrahepatic activation of coagulation (IAOC) will be instrumental in the development of effective therapies against liver disease. Using a mouse model of concanavalin A (ConA)-induced hepatitis, in which IAOC plays an essential role in causing liver injury, we uncovered a procoagulant function of chitinase 3-like 1 (Chi3l1). Chi3l1 expression is dramatically elevated after ConA challenge, which is dependent on ConA-induced T cell activation and the resulting interferon γ and tumor necrosis factor α productions. Compared with wild-type mice, Chi3l1-/- mice show less IAOC, reduced tissue factor (TF) expression, and attenuated liver injury. Reconstituting Chi3l1-/- mice with recombinant TF triggers IAOC and augments liver injury. CONCLUSION: Our data demonstrate that Chi3l1, through induction of TF via mitogen-activated protein kinase activation, promotes IAOC and tissue injury. (Hepatology 2018;67:2384-2396).
Coagulation is a critical component in the progression of liver disease. Identification of key molecules involved in the intrahepatic activation of coagulation (IAOC) will be instrumental in the development of effective therapies against liver disease. Using a mouse model of concanavalin A (ConA)-induced hepatitis, in which IAOC plays an essential role in causing liver injury, we uncovered a procoagulant function of chitinase 3-like 1 (Chi3l1). Chi3l1 expression is dramatically elevated after ConA challenge, which is dependent on ConA-induced T cell activation and the resulting interferon γ and tumor necrosis factor α productions. Compared with wild-type mice, Chi3l1-/- mice show less IAOC, reduced tissue factor (TF) expression, and attenuated liver injury. Reconstituting Chi3l1-/- mice with recombinant TF triggers IAOC and augments liver injury. CONCLUSION: Our data demonstrate that Chi3l1, through induction of TF via mitogen-activated protein kinase activation, promotes IAOC and tissue injury. (Hepatology 2018;67:2384-2396).
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