Chemokines in Chronic Liver Allograft Dysfunction Pathogenesis and Potential Therapeutic Targets

Table 2

Chemokines involved in the pathogenesis of liver disease.

Chemokine	Location in the liver	Function	Receptors and their distribution
CXC  subfamily
CXCL1	Hepatocytes, Kupffer cells, activated stellate cells; and endothelial cells [33, 34]	Neutrophil migration, innate immunity, acute inflammation, and angiogenesis	CXCR1: PMN, monocytes, and mast cells; CXCR2: PMN, monocytes, and mast cells
CXCL2	Hepatocytes, Kupffer cells, activated stellate cells; and endothelial cells [34, 35]	Neutrophil migration, innate immunity, acute inflammation, and angiogenesis	CXCR2: PMN, monocytes, and mast cells
CXCL3	Hepatocytes, Kupffer cells, activated stellate cells, and endothelial cells [33, 34]	Neutrophil migration, innate immunity, acute inflammation, and angiogenesis	CXCR2: PMN, monocytes, and mast cells
CXCL4	Sinusoidal endothelium,; platelets, NK cells, T cells, and neutrophils [36]	Chemotactic for neutrophils, monocytes, and fibroblasts	CXCR3: memory T cells, Th1, Th2, Th17, and Treg, NKT
CXCL4L1	Thrombin-stimulated platelets [37]	Angiogenesis and; antitumoral chemokine	CXCR3: memory T cells, Th1, Th2, Th17, Treg, and NKT
CXCL5	Hepatocytes, Kupffer cells, and endothelial cells [33]	Neutrophil migration, innate immunity, acute inflammation, and angiogenesis	CXCR2: PMN, monocytes, and mast cells
CXCL6	Microvascular endothelial cells [38]	Neutrophil migration and innate immunity	CXCR1: PMN, monocytes, and mast cells; CXCR2: PMN, monocytes, and mast cells
CXCL7	Platelets [39]	Angiogenesis, innate immunity, neutrophil migration, and regenerating vascular integrity after injury	CXCR1: PMN, monocytes, and mast cells; CXCR2: PMN, monocytes, and mast cells
CXCL8	Endothelial cells, Kupffer cells, biliary epithelial cells, and stellate cells [34]	Innate immunity, neutrophil migration, and angiogenesis	CXCR1: PMN, monocytes, and mast cells; CXCR2: PMN, monocytes, and mast cells
CXCL9	Sinusoidal epithelial cells [40]	Th1, Th2, Th17, and Treg recruitment and adaptive immunity	CXCR3: memory T cells, Th1, Th2, Th17, Treg, and NKT; CCR3: eosinophils and basophils
CXCL10	Hepatocytes and liver sinusoids [15]	Th1, Th2, Th17, and Treg recruitment and adaptive immunity	CXCR3: memory T cells, Th1, Th2, Th17, Treg, and NKT; CCR3: eosinophils and basophils
CXCL11	Liver sinusoids [15]	Th1, Th2, Th17, and Treg recruitment and adaptive immunity	CXCR3: memory T cells, Th1, Th2, Th17, Treg, and NK; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells, and NK
CXCL12	Biliary epithelium [15]	Stem cell migration and B-cell lymphopoiesis	CXCR4: T and B cells, monocytes, stem cells, and NKT
CXCL13	Lymphocytes within microenvironments [41]	B-cell homing in lymphoid organ and liver and T-cell homing in the liver	CXCR5: B cells; CXCR3: memory T cells, Th1, Th2, Th17, Treg and NKT
CXCL14	Macrophage and neutrophil [42]	Recruitment of monocytes/macrophages to the liver	Unknown
CXCL16	Liver sinusoids biliary epithelium [15]	T-cell migration, recruitment of CD4+ T cells, and CD8+ T cells and B cells into the liver	CXCR6: memory T cells, Th1, NK and NKT
CXCL17	Endothelial cells and hepatocellular carcinoma (HCC) cells [43]	Chemoattract DC and monocytes, angiogenesis, and carcinogenesis	Unknown
CC  subfamily
CCL1	Hepatocytes, hepatic stellate cells, endothelium, and Kupffer cells [44]	T-cell trafficking and Th2 response	CCR8: monocytes, Th2, Treg and NK
CCL2	Hepatocytes, Kupffer cells, and stellate cells [44]	Th1 inflammation, T-cell and monocyte migration, and innate and adaptive immunity	CCR2: monocytes, memory T cells, basophils and pDC
CCL3	Portal vessels, biliary epithelium, and sinusoidal endothelium [45, 46]	T-cell and monocyte migration, innate and adaptive immunity, inflammation,Th1 response, HIV infection, and hypersensitivity	CCR1: monocytes, memory T cells, Th1 and NK; CCR5: monocytes, Th1 cells and NK
CCL4	Portal vessels, biliary epithelium, and sinusoidal endothelium [15]	Th1 response, adaptive immunity, inflammation, HIV infection	CCR5: monocytes, Th1 cells and NK
CCL5	Portal vessels, platelets, T-cells, macrophages, liver-derived dendritic cells, and Kupffer cells [15]	T cell and monocyte migration, innate and adaptive immunity, inflammation, Th1 response, and HIV infection, and hypersensitivity	CCR1: monocytes, memory T cells, Th1 and NK; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells and NK
CCL7	Portal vessels, monocytes, endothelial cells, smooth muscle cells, and human CD34­ cells [47]	T-cell, NK cells, dendritic cells, basophils, eosinophils, and monocyte migration, innate and adaptive immunity, Th1 inflammation, and; hypersensitivity	CCR1: monocytes, memory T cells, Th1, and NK; CCR2: monocytes, memory T cells, basophils and pDC; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells, and NK
CCL8	Portal and vascular; endothelium [47]	T-cell and monocyte migration, innate and adaptive immunity, Th1 inflammation, hypersensitivity, and HIV infection	CCR1: monocytes, memory T cells, Th1, and NK; CCR2: monocytes, memory T cells, basophils, and pDC; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells, and NK
CCL11	Foetal liver [48]	Eosinophil and basophil migration, allergic inflammation, and Th2 response	CCR2: monocytes, memory T cells, basophils, and pDC; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells, and NK; CXCR3: memory T cells, Th1, Th2, Th17, Treg, and NKT
CCL12	Kupffer cells [49]	Monocytes, T-cell and eosinophils migration, and allergic inflammation	CCR2: monocytes, memory T cells, basophils, and DC
CCL13	Epithelial and endothelial cells [50]	T-cell and monocyte migration, innate and adaptive immunity, and Th1 inflammation	CCR1: monocytes, memory T cells, Th1, and NK; CCR2: monocytes, memory T cells, basophils, and pDC; CCR3: eosinophils and basophils
CCL14	Widely in liver and plasma [14]	T-cell and monocyte migration, hypersensitivity, innate and adaptive immunity, and inflammation	CCR1: monocytes, memory T cells, Th1, and NK; CCR3: eosinophils and basophils; CCR5: monocytes, Th1 cells, and NK
CCL15	Widely in liver [51]	T-cell, eosinophil, basophil, and monocyte migration, Th2 response, hypersensitivity, innate and adaptive immunity, and allergic inflammation	CCR1: monocytes, memory T cells, Th1, and NK; CCR3: eosinophils and basophils
CCL16	Hepatocytes and biliary epithelial cells [52]	T-cell, eosinophil, basophil, and monocyte migration,Th2 response, hypersensitivity, innate and adaptive immunity, and allergic inflammation	CCR1: monocytes, memory T cells, Th1, and NK; CCR3: eosinophils and basophils
CCL17	Keratinocytes, fibroblasts,; stimulated monocytes, and certain DC [53]	T-cell and monocyte migration, allergic inflammation, and Treg retention	CCR4: Th2 cells, Treg eosinophils, basophils, DC, and Treg
CCL18	Portal area of livers with hepatitis C but not in normal livers [54]	Lymphocytes and immature DC activation	CCR3: eosinophils and basophils
CCL19	Portal-associated; lymphoid tissue [15]	T-cell and DC homing to secondary lymphoid tissue and lymphoid development	CCR7: naive T, B, mature mDC, Th1, Th2, and Treg
CCL20	Endothelial cells,; macrophages, and DC in the livers [55]	DC migration, memory T-cells, and Th17 cells at site of inflammation	CCR6: memory T cells, B cells, Th17, and immature mDC
CCL21	Portal-associated; lymphoid tissue [15]	T-cell and DC homing to secondary lymphoid tissue; lymphoid development; T-cell recruitment; adaptive immunity; and Th1, Th2, Th17, and Treg inflammation	CXCR3 (mouse): memory T cells, Th1, Th2, Th17, Treg, and NKT; CCR7: naive T, B, mature mDC, Th1, Th2, and Treg
CCL22	DC, B cell, and macrophages (Kupffer cells) [56]	T-cell and monocyte migration, allergic inflammation, Treg retention, and T-cell skin homing	CCR4: Th2 cells, Treg eosinophils, basophils, DC, and Treg
CCL23	Macrophages (Kupffer cells) [57]	Chemotactic activity on resting T cell, monocytes, and neutrophils	CCR1: monocytes, memory T cells, Th1, and NK
CCL24	Lower levels in the liver [58]	Eosinophil and basophil migration, allergic inflammation, and Th2 response	CCR3: eosinophils and basophils
CCL25	macrophages, Kupffer cells, DC, and cholangiocytes [59]	Recruitment of adaptive immune cells to the liver. T-cell homing to gut and thymus and tolerogenic DC	CCR9: DC, memory T cells, and thymocytes
CCL26	Vascular endothelial cells [60]	Eosinophil and basophil migration, allergic inflammation, and Th2 response	CCR3: eosinophils and basophils
CCL27	No expression in liver and predominantly in the skin keratinocytes [61]	T-cell trafficking in the skin	CCR10: memory T cells and Treg
CCL28	Biliary epithelium (cholangiocytes) [15]	T-cell homing to skin and bowel	CCR10: memory T cells and Treg
C  subfamily
XCL1	Not expressed in human liver [62]	NK-cell recruitment	XCR1: NK
XCL2	Preferentially in CD8+ T cells [63]	NK-cell recruitment	XCR1: NK
CX3C  subfamily
CX3CL1	Biliary epithelium [64]	Th1 inflammation, T-cell, NK cell trafficking and adhesion, and innate and adaptive immunity	CX3CR1: monocytes, and Th1, NK

CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; CCL: C-C motif chemokine ligand; CCR: C-C motif chemokine receptor; XCL: X-C motif chemokine ligand; XCR: X-C motif chemokine receptor; CX3CL: C-X3-C motif chemokine ligand; CX3CR: C-X3-C motif chemokine receptor; Th1: T helper 1; Th2: T helper 2; Th17: T helper 17; Treg: regulatory T cell; NK: natural killer; NKT: natural killer T; DC: dendritic cell; pDC: plasmacytoid dendritic cell; mDC: myeloid dendritic cell; PMN: polymorphs.