CCR1 and CCR5 promote hepatic fibrosis in mice.
Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1alpha, MIP-1beta, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine-induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.
Seki
Ekihiro
E
Department of Medicine, Columbia University, New York, New York 10032, USA. ekseki@ucsd.edu
De Minicis
Samuele
S
Gwak
Geum-Youn
GY
Kluwe
Johannes
J
Inokuchi
Sayaka
S
Bursill
Christina A
CA
Llovet
Josep M
JM
Brenner
David A
DA
Schwabe
Robert F
RF
D000818:Animals; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement; D006801:Humans; D007728:Kupffer Cells / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology*
C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D019713:Receptors, CCR5