Chemokine Receptors CXCR3 and CCR6 and Their Ligands in the Liver and Blood of Patients with Chronic Hepatitis C

Abstract

We performed a comprehensive analysis of CCR6 and CXCR3 chemokine receptors and their ligands CCL20/MIP-3α, CXCL9/MIG, CXCL10/IP-10, and CXCL11/ITAC in the liver and blood of patients with chronic hepatitis C at different stages of the disease. TaqMan PCR was used to determine mRNA gene expression of chemokines and their receptors in liver specimens, xMAP multiplex analysis was performed to estimate the concentration of chemokines in blood plasma, and fl ow cytofluorometry was used to evaluate CCR6 and CXCR3 expression on peripheral blood lymphocyte populations. In the liver of patients with hepatitis C, mRNA expression of CXCL10, CCR6, and CXCR3 genes increases with fibrosis progression in the liver tissue. In the plasma, concentrations of all studied chemokines increased depending on the stage of liver fibrosis, CCR6 and CXCR3 expression was changed in various lymphocyte populations. Thus, chemokines are involved in the immunopathogenesis and fibrogenesis in chronic viral hepatitis C. The results suggest using these chemokines in the diagnosis and prognosis of the disease.

Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis

“…However, the stimuli that attract Th17 cells to the liver are not completely elucidated. What is known is that injured liver cells secrete a variety of chemokines, such as CXCL9, CXCL10, and CCL20 ( 119 , 120 ), that drive the recruitment of Th17 cells to the liver, binding to their receptors (CXCR3 and CCR6) expressed in Th17 cells ( 16 , 119 – 123 ). This aggregate of chemokines and their receptors seems to determine, the differential cellular recruitment ( 32 , 123 , 124 ), the disposition of the Th17 cells within fibrosis areas ( 16 , 60 , 119 , 120 ); and CXCL10, in particular, has itself a profibrotic effect influencing in the number and activity of HSCs, and participating in the cross talk between hepatocytes, HSCs, and immune cells ( 124 – 126 ).…”

“…These activated cells, using the NF-κB and MAPK signaling pathways, produce the proinflammatory cytokines IL-1, IL-6, IL-21, and IL-23 ( 38 , 93 , 107 ) that drive the Th17 differentiation and IL-17 production in peripheral blood ( 93 , 104 , 107 , 108 ). In the liver, injured cells secrete a variety of chemokines like CXCL9, CXCL10, and CCL20 ( 119 , 120 ) that drive the recruitment of Th17 cells to the liver, through binding to their receptors (CXCR3 and CCR6) expressed in Th17 cells ( 120 – 123 ). Intrahepatic Th17 cells and IL-17 are responsible for hepatic stellate cell activation ( 13 , 17 ), increased expression of TGF-β ( 127 ), MMP ( 13 , 127 , 130 ), collagen synthesis ( 13 , 127 ), and induction of EMT ( 115 , 137 , 142 ).…”

Ccr6 Deficiency Attenuates Spontaneous Chronic Colitis in Winnie

“…In addition to having pathology within the gastrointestinal tract, IBD patients also exhibit secondary organ pathologies termed as extraintestinal manifestations [12]. The spleen, liver and kidneys which are immune-related organs of secondary lymphoid origin were examined as they cause the systemic diseases-hepatitis and glomerular nephritis, where CCR6 plays a pivotal role in initiating inflammation [13][14][15][16]. Renal histology remained normal and unaffected by the Ccr6-gene ablation although there have been reports on Ccr6-deficiency having aggravated renal injury and increased mortality among nephritic mice because compared with the WT, Ccr6-deficiency in mice had reduced infiltration of regulatory T cells (Treg cells) and TH17 cells but not the TH1 type [27].…”

“…In addition to having pathology within the gastro-intestinal tract, IBD patients also exhibit secondary organ pathologies termed as extraintestinal manifestations [12]. The spleen, liver and kidneys which are immune-related organs of secondary lymphoid origin were examined as they cause the systemic diseases-hepatitis and glomerular nephritis, where CCR6 plays a crucial role in initiating inflammation [13][14][15][16].…”

Ccr6 Deficiency Attenuates Spontaneous Chronic Colitis in Winnie

“…In addition to having pathology within the gastrointestinal tract, IBD patients also exhibit secondary organ pathologies termed as extraintestinal manifestations (23). The spleen, liver and kidneys which are immune-related organs of secondary lymphoid origin were examined as they cause the systemic diseases -hepatitis and glomerular nephritis, where CCR6 plays a pivotal role in initiating inflammation (24), (25), (26), (27). Renal histology remained normal and unaffected by the Ccr6-gene ablation although there have been reports on Ccr6 -deficiency having aggravated renal injury and increased mortality among nephritic mice because compared with the WT, Ccr6 -deficiency in mice had reduced infiltration of regulatory T cells (Treg cells) and TH17 cells but not the TH1 type (28).…”