Table 1:

Chemokines in cardiac fibrosis

Chemokine	Chemokine receptors	Cellular source in models of cardiac fibrosis	Cellular targets and effects	References
CCL2	CCR2, CCR4	Macrophages, endothelial cells and fibroblasts have been reported as major sources of CCL2 in remodeling hearts. CCL2 upregulation in stressed and injured cardiomyocytes has also been demonstrated.	The fibrogenic actions of CCL2 likely involve recruitment of proinflammatory and fibrogenic CCR2+ monocytes and macrophages. May directly activate fibroblasts; however, the in vivo significance of such effects is unclear. Has been suggested to recruit fibroblast progenitors. May also promote arteriogenesis.	[27],[30],[32],[33],[24],[25]
CCL3	CCR1, CCR4, CCR5	In a model of myocarditis, macrophages and dendritic cells were the main source of CCL3.	May stimulate recruitment of pro-inflammatory leukocytes that may promote fibrosis. In myocarditis, CCL3 was found to play a critical role in virus-induced inflammation.	[99],[100],[101]
CCL4	CCR5, CCR8	CCL4 is upregulated in infarcted and remodeling hearts; however its cellular localization has not been systematically studied. Macrophages, endothelial cells and fibroblasts are likely cellular sources.	Although CCL4 is upregulated in injured and fibrotic hearts, its role in myocardial biology remains unknown.	[48]
CCL5	CCR5, CCR3, CCR1	Although many cell types (including macrophages, platelets, endothelial cells and fibroblasts) are known to produce CCL5, its cellular localization in fibrotic hearts has not been studied.	In a model of infarction, CCL5 was found to promote fibrosis, likely by accentuating inflammatory injury. May form heteromers with α-defensin, stimulating leukocyte recruitment. CCR5-mediated recruitment of anti-inflammatory leukocyte subsets has been suggested to restrain inflammation following infarction.	[47],[46],[48]
CCL24	CCR3	In myocarditis, macrophages were the main cellular source of CCL24. CCL24 levels were markedly increased in regenerating neonatal mouse hearts. However, its cellular localization has not been studied.	Although CCL24 has been implicated in fibrosis in other organs, whether it is involved in myocardial fibrosis is unknown. In eosinophilic myocarditis. CCL24 may promote fibrosis by recruiting eosinophils.	[53],[52]
CXCL8	CXCR1, CXCR2	Leukocytes, endothelial cells were found to be major sources of CXCL8 in infarcted and remodeling hearts. Fibroblasts and lymphocytes are also capable of secreting CXCL8.	May promote fibrosis by recruiting and activating neutrophils. Fibrogenic actions of CXCL8-activated neutrophils may involve formation of neutrophil extracellular traps (NETs). CXCL8 may also exert angiogenic actions.	[102],[103]
CXCL1 and other CXCR2 ligands	CXCR2	Macrophages, vascular cells, fibroblasts and mast cells can produce CXCR2 ligands.	CXCR2 ligands may promote fibrosis through recruitment of fibrogenic leukocyte subsets. CXCR2-mediated inflammation may indirectly promote fibrosis by increasing systemic blood pressure.	[23],[56],[55]
CXCL4	CXCR3	Platelets, macrophages	Although the involvement of CXCL4 in cardiac fibrosis has not been systematically studes, exogenous CXCL4 was found to increase MMP activity and to inhibit macrophage phagocytosis. CXCL4 may also be involved in lymphocyte recruitment.	[63], [65]
CXCL10	CXCR3, PG	Endothelial cells, leukocytes	CXCL10 exerts anti-fibrotic actions, inhibiting fibroblast migration and has also been suggested to have angiostatic properties. May also be involved in recruitment of lymphocytes.	[60],[61],[62]
CXCL12	CXCR4, CXCR7	Vascular cells, leukocytes, fibroblasts and cardiomyocytes	CXCL12 exerts a wide range of actions on all cell types involved in cardiac remodeling. Effects on inflammatory leukocyte recruitment, angiogenesis (through recruitment of progenitors), and cardiomyocyte survival have been reported. Fibrogenic actions may involve direct effects on fibroblast migration, or activation of fibrogenic macrophages.	[71],[72],[73],[74],[75],[76],[77],[78],[104]
CX3CL1	CX3CR1	Endothelial cells, macrophages	In a model of viral myocarditis, CX3CR1 was found to inhibit fibrosis; however, the cellular basis for these effects is unclear. In other tissues both fibrogenic and anti-fibrotic actions of CX3CL1 have been reported. Although macrophages are the most likely cellular targets of CX3CL1 in fibrotic and remodeling hearts, some experimental studies have suggested actions on many different cell types, including cardiomyocytes, fibroblasts and endothelial cells.	[83], [84]