The Role of CXCR3 in the Induction of Primary Biliary Cirrhosis

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.

Comparative proteomics study on liver mitochondria of primary biliary cirrhosis mouse model

“…Studies have shown that TLR3 pathway is critical in the pathogenesis of PBC [24-26], and poly I:C, a synthetic double-stranded RNA, can mimic the infection of retroviral RNA by interacting with TLR3 and consequently activating the innate immunity with series of cytokine production and activation of lymphocytes. This mouse model has been repeatedly constructed by a number of laboratories for uncovering the cellular and molecular events in pathogenesis of PBC [12-14]. Similar to others, our model also exhibited lymphocyte infiltration to the portal area as early as 4 weeks after initiation of poly I:C injection, and at the end of 12 weeks the model was still at stage I.…”

“…Mouse models have been served as powerful tools in the pathogenesis research of various diseases. Okada et al reported that consecutive administration of Poly I:C to C57BL/C induced PBC like lesions and serological AMA similar to features of PBC [11], and was considered as mouse model for research at the early stage of PBC [12-14]. …”

Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury

“…Mice deficient in chemokine receptors CCR1, CCR5, CCR2 and CCR7 demonstrate a decrease in the extent of injury in both chronic fibrotic and acute necrotic liver injury. Alternatively, some chemokine axes appear to be protective and their loss leads to worse outcomes in models of liver disease …”

NI‐0801, an anti‐chemokine (C‐X‐C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid

“…Apart from CXCL10, CXCR3 can also be activated by the chemokines CXCL9 and CXCL11 . It has been shown that the neutralization of CXCL10 in animal models of liver disease reduces inflammation and fibrosis and that CXCR3 deficiency delays and reduces progression of cellular inflammation in an autoimmune cholangitis animal model . However, existing animal models for PBC only have limited predictability, and we cannot exclude that interfering with CXCL10 alone might not be sufficient to reduce the entry of inflammatory cells into the liver to an extent that a clinical response can be achieved in patients with PBC.…”