The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes

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)

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

“…However, previous studies in disease models of liver, CNS, gut, and arteriosclerotic vessels (74) demonstrated that CX 3 CR1 signaling increased rather than reduced the life span of macrophages. In contrast to these findings, one recent study reported increased macrophage numbers and liver fibrosis in CX 3 CR1-deficient mice after surgical bile duct ligation, a model that resembles UUO by being induced by mechanic tissue damage (50). The discrepancy between macrophage accumulation and decreased macrophage life span in that study was suggested to have resulted from the release of proinflammatory mediators from CX 3 CR1-deficient dying macrophages that attracted further profibrotic macrophages.…”

“…Also, CX 3 CR1 has been implicated in monocyte recruitment into inflamed tissues, like arteriosclerotic vessels (45), the listeria-infected spleen (46), the eye (47), in colitis models (28), or the skin (48). Furthermore, CX 3 CR1 may exert profibrotic functions (49)(50)(51)(52)(53)(54)(55).…”

“…Also, studies on human biopsy material from fibrotic kidneys described upregulation of CX 3 CR1, supporting a pathogenic role (59). However, in toxin-and in obstruction-induced liver fibrosis, CX 3 CR1 was protective (50). The role of CX 3 CR1 in the obstruction-induced standard kidney fibrosis model, UUO, has not been clarified yet.…”

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

“…390439; MP Biomedicals, Solon, OH) (8). Biochemical assays and gene and protein expression studies were performed as described previously (8,24,25).…”

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…30 Its role in aortic accumulation of other leukocytes has not been reported. Second, CX3CR1 inhibits apoptosis of smooth muscle cells 31 2/2 macrophages undergo excess cell death in hepatic fibrosis 36 and renal candidiasis 37 and fibrosis. 38 CX3CR1 is upregulated on T cells in inflammation, CX3CR1 protects T H2 and T H1 cells from apoptosis, and cytokine production is higher in CX3CR1 + than CX3CR1 -T H1 cells.…”