CXC chemokine receptor-1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury

Abstract

CXC chemokines mediate hepatic inflammation and injury following ischemia/reperfusion (I/ R). More recently, signaling through CXC chemokine receptor-2 (CXCR2) was shown to delay liver recovery and repair after I/R injury. The chemokine receptor CXCR1 shares ligands with CXCR2, yet nothing is known about its potential role in liver pathology. In the present study, we examined the role of CXCR1 in the injury and recovery responses to I/R using a murine model. CXCR1 expression was undetectable in livers of sham-operated mice. However, after ischemia CXCR1 expression increased 24 hours after reperfusion and was maximal after 96 hours of reperfusion. CXCR1 expression was localized largely to hepatocytes. In order to assess the function of CXCR1, CXCR22/2 mice were treated with the CXCR1/CXCR2 antagonist, repertaxin. Prophylactic treatment with repertaxin had no effect on acute inflammation or liver injury. However, when repertaxin was administered 24 hours postreperfusion there was a significant increase in hepatocellular injury and a delay in recovery compared to control-treated mice. CXCR12/2 mice also demonstrated delayed recovery and regeneration after I/R when compared to wild-type mice. In vitro, hepatocytes from CXCR2 2/2 mice that were stimulated to express CXCR1 showed increased proliferation in response to ligand. Hepatocyte proliferation was decreased in CXCR1 2/2 mice in vivo. Conclusion: This is the first report to show that CXCR1 expression is induced in hepatocytes after injury. Furthermore, the data suggest that CXCR1 has divergent effects from CXCR2 and appears to facilitate repair and regenerative responses after I/R injury. (HEPATOLOGY 2011;53:261-271) I schemia/reperfusion (I/R) of the liver often occurs as a result of liver resection surgery, transplantation, and trauma, and is a primary cause of subsequent liver dysfunction.1-3 The recovery and regeneration of the liver after I/R is associated with the temporal expression of cell cycle control proteins. 4 Recent data from our laboratory has demonstrated that this process is regulated by signaling through CXC chemokine receptor-2 (CXCR2). 5 These studies demonstrated that deletion or pharmacological blockade of CXCR2 increased hepatocyte proliferation and liver regeneration in association with increased activation of the transcription factors, nuclear factor-jB (NF-jB) and signal transducer and activator of transcription-3 (STAT3). Furthermore, we showed that ligands of CXCR2 have direct, dose-dependent effects on hepatocytes to regulate cell death or proliferation. 5The ligands for CXCR2 are comprised of a subclass of CXC chemokines which possess the amino acid sequence Glu-Leu-Arg (ELR motif ) in the amino terminus.6,7 However, CXCR2 is not the only receptor for ELR þ CXC chemokines. In humans, CXC chemokine receptor-1 (CXCR1) also binds many of these ligands and has both overlapping and independent Abbreviations: ALT, alanine amino transferase; BrdU, 5-bromo-2 0 -deoxyuridine; CXCR1, CXC chemokine receptor-1; CXCR2, CXC chemokine receptor-...

Branches of NF-κb signaling pathway regulate hepatocyte proliferation in rat liver regeneration

“…The activities of physiological processes reflected by expression changes were analyzed by systems biology methods, and both the chemotactic factor branches and its regulation of hepatocyte proliferation activity were found increased in rat liver regeneration (Figure 1). This result was consistent with the conclusion of Van Sweringen et al (2011), who demonstrated the correlation between the signal transduction activity of the chemotactic factor branch of the NF-κB signaling pathway and hepatocyte proliferation activity (Clarke et al, 2011;Van Sweringen et al, 2011). The above results led to the speculation that the downregulation of Cxcl12 and upregulation of its receptor-activated gene Gnail and its homologous genes Bf289002 together activate transcription factor NF-κB family member Rela's homologous gene Bf419700, which augment hepatocyte proliferation activity by upregulating the expression of cell proliferation-promoting genes Ccnd1, Myc, and Timp1 and downregulating the expression of cell proliferation-inhibiting gene Dusp1, ultimately enhancing hepatocyte proliferation.…”

CXC Chemokines Function as a Rheostat for Hepatocyte Proliferation and Liver Regeneration

“…CXC chemokines containing the ELR motif bind to the receptors CXCR1 and CXCR2 and have been shown regulate liver repair and regeneration [5–11]. Of particular interest is the fact that this ligand/receptor system has been shown to have divergent effects on liver regeneration that is dependent upon the insult.…”

CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice

“…We previously showed that specific members of the CXC chemokine family are critical mediators in all aspects of the injury, repair, and regeneration processes (2,4,5,17). Our previous work focused on CXC chemokines that contain a glutamic acid-leucinearginine (ELR) motif in their amino terminus, which confers binding specificity to the receptors CXCR1 and CXCR2 (2,17). However, other CXC chemokines may also be involved in the response to hepatic I/R injury.…”

“…The ischemic insult induces an inflammatory response resulting in acute liver injury that is followed by a reparative phase and subsequent liver regeneration mediated by a complex interaction of growth factors, cytokines, and transcriptional factors (7,22). We previously showed that specific members of the CXC chemokine family are critical mediators in all aspects of the injury, repair, and regeneration processes (2,4,5,17). Our previous work focused on CXC chemokines that contain a glutamic acid-leucinearginine (ELR) motif in their amino terminus, which confers binding specificity to the receptors CXCR1 and CXCR2 (2,17).…”