The Role of CXCR3 in the Induction of Primary Biliary Cirrhosis

Wen Zhang,Jinming Gao,Yunyun Fei,Fengchun Zhang,Bin Liu

doi:10.1155/2011/564062

Abstract

Objective. Investigate whether CXCR3 and its ligands were involved in the pathogenesis of primary biliary cirrhosis (PBC) in an autoimmune cholangitis animal model. Methods. Female C57BL/6 mice were injected with 5 mg/kg of poly I:C intraperitoneally twice a week for 24 weeks. PBC model was confirmed by liver function, serum autoantibodies and liver biopsy. Lymphocytes subsets in liver and spleen and CXCL10 serum level were tested by flow cytometry and ELISA. Liver specimens were collected to evaluate the differences in pathology between WT and CXCR3−/− mice. Results. Antimitochondrial antibody was detected in all PBC model. Numbers of infiltrates were detected in the portal areas 8 weeks after poly I:C injection, which progressed up to 24 weeks. Compared to control mice, CXCL10 serum level increased in PBC mice and the proportion of CXCR3+ cells increased in the intrahepatic infiltrates of PBC mice, chiefly on CD8+ cells, whereas the expression of CXCR3 on CD3+ and CD8+ splenocytes decreased in PBC model. Compared with WT mice, CXCR3−/− mice developed delayed and milder progression of cellular inflammation. Conculsions. CXCR3 might contribute to the development of PBC in murine model. Knockout of CXCR3 might delay and alleviate the PBC disease progression, but could not entirely block the disease development.

Highlights

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease characterized by chronic, progressive destruction of small intrahepatic bile duct with portal inflammation and fibrosis
Four groups of C57BL/6 background mice, 10 to 12 weeks old (20–22 grams of weight), 24 in each group, were used for this experiment: Group I, WT control mice, which were injected intraperitoneally with sterilized phosphatebuffered saline (PBS); Group II, CXCR3−/− control mice, which were injected with PBS; Group III, WT PBC mice, which were injected with Polyinosinic polycytidylic acid (Poly I:C) and Group IV, CXCR3−/− PBC mice, which were injected with poly I:C
To determine whether distinct subsets of peripheral immune cells are selectively recruited to the liver, we examined the expression of CXCR3 on liver-infiltrating lymphocytes at week 8, 16 and 24 (Figure 4) by flow cytometry which demonstrated a significantly higher proportion of CXCR3 expressed on CD3+, CD4+ and CD8+ cells in liver than in spleen, especially in the WT PBC model mice

Summary

Introduction

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease characterized by chronic, progressive destruction of small intrahepatic bile duct with portal inflammation and fibrosis. Chemokines played a significant role in regulating the development, differentiation, and location of leukocytes, controlling the migration of immune cells. It was reported that CX3CL1 played great role in biliary inflammation in primary biliary cirrhosis [3]. CXCR3, one of the chemokine receptors, was found predominantly on T cells has three different ligands: IFN-inducible protein 10 (IP-10)/CXCL10, monokine induced by IFN-γ (Mig)/CXCL9, and IFN-inducible T cell α chemoattractant (ITAC)/CXCL11 [4,5,6], playing a critical role in the recruitment of T cells to inflammatory sites and regulating T cell activation [7]

Methods

Results

Conclusion