| First Author | Chen L | Year | 2019 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 7 |
| Issue | 3 | Pages | 623-639 |
| PubMed ID | 30630119 | Mgi Jnum | J:295289 |
| Mgi Id | MGI:6453793 | Doi | 10.1016/j.jcmgh.2018.12.009 |
| Citation | Chen L, et al. (2019) Deletion of C-C Motif Chemokine Ligand 5 Worsens Invariant Natural Killer T-Cell-Mediated Hepatitis via Compensatory Up-regulation of CXCR2-Related Chemokine Activity. Cell Mol Gastroenterol Hepatol 7(3):623-639 |
| abstractText | BACKGROUND & AIMS: Chemokine-mediated immune cell recruitment plays pivotal roles in liver inflammation. C-C motif chemokine ligand 5 (CCL5) has been shown to be responsible for the recruitment of monocytes/macrophages and has been implicated in various liver diseases, including nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma. Previous studies have also shown that inhibition of CCL5 appears to be a promising therapeutic approach for several chronic liver diseases. However, whether blocking CCL5 could benefit immune cell-mediated hepatitis remains largely elusive. METHODS: By adopting a specific agonist, alpha-galactosylceramide (alpha-Galcer), of invariant natural killer T cells (iNKTs), we investigated the function and mechanism of CCL5 in the iNKT induced murine hepatitis model. RESULTS: We found significantly increased CCL5 expression in alpha-Galcer-induced hepatitis murine model. Such an increase in CCL5 is mainly enriched in non-parenchymal cells such as macrophages and iNKTs but not in hepatocytes. Surprisingly, CCL5 blockage by genetic deletion of Ccl5 does not affect the alpha-Galcer-induced iNKT activation but greatly worsens alpha-Galcer-induced liver injury accompanied by an increased hepatic neutrophil infiltration. Mechanistically, we demonstrated that greater neutrophil accumulation in the liver is responsible for the enhanced liver injury in Ccl5(-/-) mice. Such an increased hepatic neutrophil infiltration is mainly caused by an enhanced CXCL1-CXCR2 signal in Ccl5(-/-) mice. Therapeutically, either antibody-mediated neutrophil depletion or a CXCR2 antagonist, SB225002, mediated CXCR2 signaling blockage significantly ameliorated alpha-Galcer-induced liver injury in Ccl5(-/-) mice. CONCLUSIONS: Our present study demonstrates that (1) alpha-Galcer-induced murine hepatitis could greatly induce CCL5 production in macrophages and iNKT cells; (2) loss of CCL5 could enhance CXCL1 expression in hepatocytes and activate CXCL1-CXCR2 axis in neutrophils to augment their hepatic infiltration; and (3) neutrophil depletion or blockage of CXCL1-CXCR2 axis greatly improves alpha-Galcer-induced liver injury in Ccl5(-/-) mice. This study suggests that clinical utilization of CCL5 blockage may compensatorily induce the activation of other chemokine pathways to enhance neutrophil recruitment and liver injury in hepatitis. |
