The Fractalkine Receptor CX3CR1 Protects Against Liver... : Hepatology (original) (raw)
Liver Failure/Cirrhosis/Portal Hypertension
The Fractalkine Receptor CX3CR1 Protects Against Liver Fibrosis by Controlling Differentiation and Survival of Infiltrating Hepatic Monocytes
Karlmark, Karlin Raja1; Zimmermann, Henning W.1; Roderburg, Christoph1; Gassler, Nikolaus2; Wasmuth, Hermann E.1; Luedde, Tom1; Trautwein, Christian1; Tacke, Frank1,*
1_Department of Medicine III, University Hospital Aachen, Aachen, Germany_
2_Institute of Pathology, University Hospital Aachen, Aachen, Germany_
*Address reprint requests to: Department of Medicine III, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. E-mail:[email protected]; fax: 49-241-80-82455
Received 26 March 2010; accepted 25 July 2010
This work was supported by the German Research Foundation (Ta434/2-1 to Frank Tacke and SFB/TRR 57).
View this article online atwileyonlinelibrary.com.
Potential conflict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.
Abstract
Chemokines modulate inflammatory responses that are prerequisites for organ fibrosis upon liver injury. Monocyte-derived hepatic macrophages are critical for the development, maintenance, and resolution of hepatic fibrosis. The specific role of monocyte-associated chemokine (C-X3-C motif) receptor 1 (CX3CR1) and its cognate ligand fractalkine [chemokine (C-X3-C motif) ligand 1)] in liver inflammation and fibrosis is currently unknown. We examined 169 patients with chronic liver diseases and 84 healthy controls; we found that CX3CL1 is significantly up-regulated in the circulation upon disease progression, whereas CX3CR1 is down-regulated intrahepatically in patients with advanced liver fibrosis or cirrhosis. To analyze the functional relevance of this pathway, two models of experimental liver fibrosis were applied to wild-type (WT) and CX3CR1-deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX3CR1−/− animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride–induced and bile duct ligation–induced fibrosis. CX3CR1−/− mice displayed significantly increased numbers of monocyte-derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX3CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX3CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor–producing and inducible nitric oxide synthase–producing macrophages. CX3CR1 represents an essential survival signal for hepatic monocyte–derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX3CR1 undergo increased cell death after liver injury, which then perpetuates inflammation, promotes prolonged inflammatory monocyte infiltration into the liver, and results in enhanced liver fibrosis.
Conclusion:
CX3CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX3CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy. (Hepatology 2010;52:1769-1782)
© 2010 by Lippincott Williams & Wilkins, Inc.