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
| Autor: | Jichang Li, Meng Li, Yankai Wen, Qiang Xia, Min Xu, Yongbing Qian, Lei Xia, Lili Chen, Yihan Qian, Xiaoni Kong, Hailong Wu, Jinyang Gu, Jia-Xin Li |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemokine Neutrophils Chemokine CXCL1 MPO myeloperoxidase AST aspartate aminotransferase Lymphocyte Activation Receptors Interleukin-8B Hepatitis Mice PCR polymerase chain reaction 0302 clinical medicine Nonalcoholic fatty liver disease CXC chemokine receptors Chemokine CCL5 Original Research Liver injury TNF tumor necrosis factor CCL5 biology Chemistry Gastroenterology iNKT invariant natural killer T cells hemic and immune systems ELISA enzyme-linked immunosorbent assay Middle Aged CXCL1 Chemokine activity HSC hepatic stellate cell CD1d-tet CD1d- α-GalCer tetramers Up-Regulation DILI drug-induced liver injury Liver Neutrophil Infiltration HCV hepatitis C virus Cytokines 030211 gastroenterology & hepatology Adult NETs neutrophil extracellular traps NKT natural killer T cell Galactosylceramides a-Galcer alpha-galactosylceramide Ccl5 C-C motif chemokine ligand 5 Young Adult 03 medical and health sciences ROS reactive oxygen species stomatognathic system ALT alanine aminotransferase parasitic diseases medicine Animals Humans IFN interferon RNA Messenger lcsh:RC799-869 Aged NPCs non-parenchymal cells CXCR2 Hepatology AIH autoimmune hepatitis Invariant NKT medicine.disease WT wild-type IL interleukin Mice Inbred C57BL Disease Models Animal stomatognathic diseases HBV hepatitis B virus MNCs mononuclear cells 030104 developmental biology Hepatocytes Cancer research biology.protein Natural Killer T-Cells lcsh:Diseases of the digestive system. Gastroenterology NAFLD nonalcoholic fatty liver disease HCC hepatocellular carcinoma Gene Deletion Spleen |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 7, Iss 3, Pp 623-639 (2019) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2018.12.009 |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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