Hepatocyte signaling through CXC chemokine receptor‐2 is detrimental to liver recovery after ischemia/reperfusion in mice†

Abstract

CXC chemokines and their receptor, CXC chemokine receptor-2 (CXCR2), are important components of the hepatic inflammatory response to ischemia/reperfusion (I/R). However, direct effects of CXC chemokines on hepatocytes during this response have not been studied. Wild-type and CXCR2 ؊/؊ mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 96 hours of reperfusion. CXCR2 ؊/؊ mice had significantly less liver injury at all reperfusion times compared with wild-type mice. Early neutrophil recruitment (12 hours) was diminished in CXCR2 ؊/؊ mice, but within 24 hours it was the same as that of wild-type mice. Hepatocyte proliferation and regeneration was accelerated in CXCR2 ؊/؊ mice compared with wild-type mice. These effects were associated with increased activation of nuclear factor B and signal transducers and activators of transcription-3, despite there being no difference in the expression of proliferative factors such as tumor necrosis factor ␣, interleukin-6, and hepatocyte growth factor. To establish whether the accelerated proliferation and regeneration observed in CXCR2 ؊/؊ mice was due to effects on hepatocytes rather than just a generalized decrease in acute inflammatory injury, mice were treated with the CXCR2 antagonist, SB225002, after neutrophil recruitment and injury were maximal (24 hours after reperfusion). SB225002 treatment increased hepatocyte proliferation and regeneration in a manner identical to that observed in CXCR2 ؊/؊ mice. Treatment of primary wild-type hepatocytes with macrophage inflammatory protein-2 revealed that low concentrations protected against cell death, whereas high concentrations induced cell death. These effects were absent in hepatocytes from CXCR2 ؊/؊ mice. Conclusion: Our data suggest that hepatocyte CXCR2 regulates proliferation and regeneration after I/R injury and reveal important differences in the role of this receptor in liver regeneration and repair induced under different conditions that may be related to ligand concentration. (HEPATOLOGY 2008;48:1213-1223

NLRP3 Regulates Neutrophil Functions and Contributes to Hepatic Ischemia–Reperfusion Injury Independently of Inflammasomes

“…Although the reason for this discrepancy is unclear, the differences between our study and the study by Kamo et al are the hepatic I/R protocol used and the extent of injury. Compared with our study and prior studies on hepatic I/R injury (13,29), it is likely that the I/R protocol by Kamo et al induced excessive inflammation and injury in the liver. These data suggest that the contribution of the inflammasome might depend on the extent of liver injury and the status of inflammatory responses after I/R.…”

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…We have previously shown that after hepatic I/R, signals for liver recovery/regeneration do not occur until after 24 h of reperfusion (3,22). Accordingly, although no differences were seen in the degree of liver injury as manifested by serum ALT levels and histology after 8 h of reperfusion in this study, TCR-␦ deficiency may have effects on liver recovery and regeneration.…”

“…The liver is one of the most abundant sources of NKT cells among the immune organs, which account for ϳ50% of total ␣␤ T cells in the liver (11). NKT cells are activated by recognizing glycolipid presentation to TCRs by CD1d, a member of the CD1 family of antigen-presenting molecules (22). Originally, it was thought that NKT cells could not play a role in postischemic tissue injury because of the absence of foreign antigen.…”

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).…”