Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

Abstract

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV-and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-bloodvessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12

“…2,25 In cirrhotic human livers, cholangiocytes, identified by cytokeratin 19, show similar distribution of staining as CXCL12 in hepatic sections from the same patient ( Figure 1A). Similarly, in normal and bile duct Figure 2 Murine and human cholangiocytes do not express CXCL12.…”

“…23e25 CXCL12, and specifically cholangiocyte-derived CXCL12, plays a role in sustaining these unique hepatic niches and promoting accumulation of periportal CXCR4-expressing lymphocytes. 2 Similar to its function in the bone marrow, hepatic CXCL12 can recruit CD34 þ bone marrow stem cells to the periportal region and may be important in sustaining a population of hematopoietic stem cells within the liver. 8 Furthermore, differential expression of CXCL12 and its receptors promotes profibrotic changes within the hepatic vascular niche during injury.…”

“…1 Specifically, in patients with liver disease, CXCL12 expression is increased in both serum and hepatic tissue proportional to the extent of injury. 2 CXCL12 expression has been documented in stellate cells, sinusoidal endothelial cells, and biliary epithelial cells (BECs) and is thought to drive inflammation and fibrogenesis, although its role, particularly in normal liver, remains largely unknown. 3 During fetal development, B-cell lymphopoiesis is dependent on hepatic CXCL12, 4 and in the adult, hepatic CXCL12 may support a hepatic hematopoietic stem cell niche.…”

“…5 Finally, with injury, immunohistochemical data demonstrate robust CXCL12 expression by proliferating bile ductules in all forms of liver injury, and biliary CXCL12 expression is further supported by the accumulation of CXCR4-positive lymphocytes in the periportal region. 2,6 A careful review of the literature, however, reveals that most data supporting BEC expression of CXCL12 are based on immunohistochemistry using a single monoclonal CXCL12 antibody (murine anti-human/mouse CXCL12, clone 79018). We believe that differentiated BECs may not express CXCL12 and that the observed pattern of BEC expression is a result of antibody crossreactivity to an epitope found in BECs.…”

“…Herein, we show that despite previous studies demonstrating robust CXCL12 expression by BECs, their role in hepatic CXCL12 production may be more limited. 2,6,8 …”