Table 2 |.
Role of chemokines in human liver diseases
| Chemokine | Receptor | Proposed role in disease | Function in animal models |
|---|---|---|---|
| ALD | |||
| CXCL1, CXCL4, CXCL5, CXCL6, CXCL8 | CXCR1, CXCR2 | Neutrophil chemoattractant; levels increased in ALD, elevated levels of CXCL1, CXCL5, CXCL6 and CXCL8 correlate with poorer clinical outcomes in alcoholic hepatitis46 | Neutralizing CXCL1 by antibodies or genetic deletion or CXCR1-CXCR2 blockade ameliorated liver inflammation in alcohol-fed mice5,103 |
| CCL2 | CCR2 | Monocyte chemoattractant; levels increased in ALD2; plasma levels and hepatic expression of CCL2 were associated with disease severity in alcoholic hepatitis99 | CCL2-knockout mice showed attenuated liver inflammation and steatosis78; pharmacological inhibition of CCL2 ameliorated steatosis development207; CCL2 might have direct effects on steatosis via PPARα78 |
| Nonalcoholic fatty liver disease | |||
| CCL2 | CCR2 | Monocyte chemoattractant; levels elevated in NASH and correlated with fibrosis in NASH217 | CCL2 overexpression in adipose tissue led to insulin resistance and hepatic steatosis116; CCR2 inhibition decreased liver macrophage infiltration and fibrosis in NASH model218,219; CCL2 directly affects adipocytes favouring lipogenesis114,115 |
| CCL5 | CCR1, CCR5 | Recruits T cells and NK cells; levels elevated in patients with NASH122 | Levels elevated in animal models of NAFLD and CCL5 pharmacological inhibitors attenuated liver steatosis122,123 |
| CXCL9, CXCL10, CXCL11 | CXCR3 | Regulate and activate T cells; elevated in NASH125; promote lipid accumulation and induce endoplasmic reticulum stress125; CXCL9 and CXCL10 levels correlate with fibrosis55,125; circulating CXCL10 levels correlated with the degree of lobular inflammation and was an independent risk factor for NASH in patients125 | Mice with CXCR3-knockout or blockade of CXCR3 showed reduced steatohepatitis in NASH model125,220; mice with CXCL10-knockout or blockade of CXCL10 were protected against diet-induced NASH125,126; CXCL10-bearing hepatocyte extracellular vesicles were chemotactic for macrophages221 |
| Cirrhosis | |||
| CCL2 | CCR2 | Monocyte chemoattractant; contributes to inflammatory responses leading to steatosis and fibrosis; CCL2 might promote hepatic stellate cell migration132 | CCL2-knockout mice showed attenuated liver injury in CCl4 injection model133 |
| CCL3, CCL4, CCL5 | CCR1, CCR3, CCR5 | Recruits T cells and NK cells; promotes liver fibrogenesis; elevated in patients with cirrhosis136,222; CCR5 may be important for hepatic stellate cell activation136 | Deletion of CCL3, CCL5, CCR1, CCR5 or CCL5 inhibition are protective against fibrosis in CCl4 injection model122,137 |
| CXCL9, CXCL10, CXCL11 | CXCR3 | Recruit T helper cells, particularly TH17 and Treg cells; elevated in patients with cirrhosis55,138; CXCL9 has antifibrogenic and CXCL10 has profibrogenic effects on hepatic stellate ceils55,140 | CXCR3-knockout mice showed increased fibrosis in a CCl4 injection model55; CXCR3 inhibition is associated with reduced fibrosis in congenital hepatic fibrosis model223 |
| CXCL16 | CXCR6 | Survival and maturation factor for NKT cells and promote NKT cell accumulation at injury site142; CXCR6 and CXCL16 expression was increased in the livers of patients with cirrhosis142 | CXCR6-knockout mice showed attenuated inflammation and fibrosis in CCl4 injection model142 |
| CX3CL1 | CX3CR1 | Promotes macrophage survival; levels elevated in cirrhosis; favours the development of anti-inflammatory macrophages143 | CX3CR1-knockout mice showed increased fibrosis in CCl4 injection model144 |
| HCC | |||
| CCL1 | CCR8 | Monocyte chemoattractant; recruit myeloid-derived suppressor cells, which inhibit anti-tumour immune surveillance147, but might also recruit anti-tumour immune cells, including CD4+ TH1 cells, CD8+ T cells and NK cells148; CCL1 level was found to be elevated in HCC and even higher in peritumoural liver tissue224; CCL2 is highly expressed in patients with HCC and is a prognostic factor for poor outcome225 | CCR2-knockout or blockade inhibits tumour growth and host survival in murine HCC model; inhibiting CCR2+ tumour-associated macrophage infiltration using pharmacological CCL2 antagonist substantially reduced tumour growth226 |
| CCL2 | CCR2 | ||
| CCL17,CCL20, CCL22 | CCR6 | Recruits Treg cells; elevated levels correlate with poorer survival in patients with HCC227; CCL20 might recruit TH17 cells as well, opposing the action of Treg cells139 | CCL20 neutralization suppressed tumour growth and metastasis in murine HCC model228 |
| CXCL12 | CXCR4, CXCR7 | Immune activation; CXCL12 was shown to have an angiogenic effect; CXCL12 can act on HCC cells and promote cell proliferation, survival and invasion160; CXCR4 and CXCR7 both implicated in tumour growth and metastasis156–161 | CXCR7 inhibition decreases angiogenesis and tumour growth in murine HCC model156; the inhibition of CXCR4 decreases angiogenesis in animal models, HCC can be stimulated to produce vascular endothelial growth factor in the presence of CXCL12 (REFS156,157) |
| CXCL16 | CXCR6 | Elevated numbers of CXCR6+ cells were seen in patients with HCC164 | Elimination of CXCR6+ NKT cells resulted in worsened HCC tumour growth in vivo162,163 |
This tabel is an abbreviated version of Supplementary Table 1. ALD, alcohol-associated liver disease; CCl4, carbon tetrachloride; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NK cells, natural killer cells; NKT cells, natural killer T cells; PPARα, peroxisome proliferator-activated receptor-α; TH, T helper; Treg, regulatory T.