CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver

Abstract

Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. CX3CL1/fractalkine is a membrane-associated chemokine that requires step processing for chemotactic activity and has been recently implicated in liver disease. Here, we investigated the potential shedding activities involved in the release of the soluble chemotactic peptides from CX3CL1 in the injured liver. We showed an increased expression of the sheddases ADAM10 and ADAM17 in patients with chronic liver diseases that was associated with the severity of liver fibrosis. We demonstrated that hepatic stellate cells (HSC) were an important source of ADAM10 and ADAM17 and that treatment with the inflammatory cytokine inter-feron-γ induced the expression of CX3CL1 and release of soluble peptides. This release was inhibited by the metalloproteinase inhibitor batimastat; however, ADAM10/ADAM17 inhibitor GW280264X only partially affected shedding activity. By using selective tissue metalloprotease inhibitors and overexpression analyses, we showed that CX3CL1 was mainly processed by matrix metalloproteinase (MMP)-2, a metalloprotease highly expressed by HSC. We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signalling pathway and promoted chemoattraction of monocytes in vitro. We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides, thereby facilitating recruitment of inflammatory cells and paracrine stimulation of HSC in chronic liver diseases.

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

“…These agents were also known to inhibit the respective target pathways in hepatic stellate cells at the concentrations used in this study. 34 In these experiments, for the first time, we obtained a result suggesting that there is a concentration-dependent inhibition of CX3CL1 secretion. This has not been observed with MCP-1.…”

CX3CL1–CX3CR1 Interaction Increases the Population of Ly6C−CX3CR1hi Macrophages Contributing to Unilateral Ureteral Obstruction–Induced Fibrosis

“…CX3CL1 is an exclusive ligand for CX3CR1 and is produced in its membrane-bound form (43)(44)(45). In the current study, we found that CX3CL1 is mainly induced in tubular cells in response to renal obstructive injury, although glomerular endothelial cells are also responsive.…”

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

“…Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. Membrane-associated chemokine CX3CL1/fractalkine soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signaling pathway and promoted chemoattraction of monocytes (Bourd-Boittin et al, 2009). HSC might also be important during the onset of hepatic tissue injury as proinflammatory elements and might interact with intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 ligand-bearing inflammatory cells, thereby modulating the recruitment and migration of mononuclear cells within the perisinusoidal space of diseased livers (Knittel et al, 1999).…”