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Background and aim: Liver injury leads to infiltration of immune cells and a subsequent activation of hepatic stellate cells. Chemokines are ubiquitous chemotactic proteins which are involved in inflammatory pathways. It has been recently suggested that chemokines can also induce the expression of other chemokines and thereby indirectly regulate immune cell recruitment. We therefore investigated the ability of the chemokine CXCL9 to induce CXCL1, an important neutrophil chemoattractant.
Methods: The ability of CXCR3 ligands CXCL9 and CXCL10 to induce CXCL1 expresssion was analyzed in immortalized (GRX) and primary hepatic stellate cells isolated from wild-type and CXCR3-/- mice. Cells were treated with different concentrations of chemokines in the absence and presence of pertussis toxin. Furthermore, mice were treated systemically with CXCL9 and hepatic CXCL1 levels as well as neutrophil infiltration were assessed.
Results: Treatment of GRX cells with CXCL9 leads to a dose dependent induction of CXCL1 protein expression. This stimulatory effect was validated in primary hepatic stellate cells (P<0.01). In contrast, stimulation of stellate cells with CCL2 did not result in CXCL1 induction. Increased CXCL1 expression in response to CXCL9 was completely abolished by co-incubation with pertussis toxin and in stellate cells derived from CXCR3-/- mice, the canonical receptor for CXCL9 and CXCL10. Notably, systemic treatment of mice with CXCL9 led to elevated hepatic CXCL1 levels and was associated with enhanced neutrophil infiltration into the liver.
Conclusions: The study describes a chemokine-chemokine pathway in hepatic stellate cells which leads to augmented infiltration of neutrophils into the liver during acute liver injury.