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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.CM

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.

Authors+Show Affiliations

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.Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.School of Pharmacy, Fudan University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: xiaoni-kong@126.com.Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China. Electronic address: wuhailong2@hotmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30630119

Citation

Chen, Lili, et al. "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." Cellular and Molecular Gastroenterology and Hepatology, vol. 7, no. 3, 2019, pp. 623-639.
Chen L, Gu J, Qian Y, et al. 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.
Chen, L., Gu, J., Qian, Y., Li, M., Qian, Y., Xu, M., Li, J., Wen, Y., Xia, L., Li, J., Xia, Q., Kong, X., & Wu, H. (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. Cellular and Molecular Gastroenterology and Hepatology, 7(3), 623-639. https://doi.org/10.1016/j.jcmgh.2018.12.009
Chen L, et al. 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. PubMed PMID: 30630119.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chen,Lili, AU - Gu,Jinyang, AU - Qian,Yihan, AU - Li,Meng, AU - Qian,Yongbing, AU - Xu,Min, AU - Li,Jichang, AU - Wen,Yankai, AU - Xia,Lei, AU - Li,Jiaxin, AU - Xia,Qiang, AU - Kong,Xiaoni, AU - Wu,Hailong, Y1 - 2019/01/07/ PY - 2018/06/01/received PY - 2018/12/29/revised PY - 2018/12/31/accepted PY - 2019/1/11/pubmed PY - 2019/6/5/medline PY - 2019/1/11/entrez KW - CCL5 KW - CXCL1 KW - CXCR2 KW - Invariant NKT KW - Neutrophils SP - 623 EP - 639 JF - Cellular and molecular gastroenterology and hepatology JO - Cell Mol Gastroenterol Hepatol VL - 7 IS - 3 N2 - 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. SN - 2352-345X UR - https://www.unboundmedicine.com/medline/citation/30630119/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-345X(19)30001-3 DB - PRIME DP - Unbound Medicine ER -