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. 2019;7(3):623-639. doi: 10.1016/j.jcmgh.2018.12.009.
Lili Chen  1 ,  Jinyang Gu  2 ,  Yihan Qian  3 ,  Meng Li  4 ,  Yongbing Qian  4 ,  Min Xu  4 ,  Jichang Li  4 ,  Yankai Wen  4 ,  Lei Xia  4 ,  Jiaxin Li  4 ,  Qiang Xia  4 ,  Xiaoni Kong  5 ,  Hailong Wu  6
Affiliations
  • 1. Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2. Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3. School of Pharmacy, Fudan University, Shanghai, China.
  • 4. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
  • 6. Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China. Electronic address: [email protected].
PMID: 30630119 DOI: 10.1016/j.jcmgh.2018.12.009
Abstract

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 (α-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 α-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 α-Galcer-induced iNKT activation but greatly worsens α-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 α-Galcer-induced Liver Injury in Ccl5-/- mice.

Conclusions: Our present study demonstrates that (1) α-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 α-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.

Keywords
CCL5; CXCL1; CXCR2; Invariant NKT; Neutrophils.
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