Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization

Cellular & Molecular Immunology volume 17, pages 753–764 (2020)Cite this article

Subjects

Abstract

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lee, W. M. Drug-induced acute liver failure. Clin. Liver Dis. 17, 575–586 (2013).

    Article  Google Scholar 

  2. Jaeschke, H., Williams, C. D., Ramachandran, A. & Bajt, M. L. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int. 32, 8–20 (2012).

    Article  CAS  Google Scholar 

  3. Dahlin, D. C., Miwa, G. T., Lu, A. Y. & Nelson, S. D. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl Acad. Sci. USA 81, 1327–1331 (1984).

    Article  CAS  Google Scholar 

  4. Jaeschke, H., Duan, L., Akakpo, J. Y., Farhood, A. & Ramachandran, A. The role of apoptosis in acetaminophen hepatotoxicity. Food Chem. Toxicol. 118, 709–718 (2018).

    Article  CAS  Google Scholar 

  5. Tran, T. & Lee, W. M. DILI: New Insights into Diagnosis and Management. Curr. Hepat. Rep. 12, (53–58 (2013).

    Google Scholar 

  6. Saito, C., Zwingmann, C. & Jaeschke, H. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51, 246–254 (2010).

    Article  CAS  Google Scholar 

  7. Barbier-Torres, L. et al. The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury. Nat. Commun. 8, 2068 (2017).

    Article  Google Scholar 

  8. Zhang, C. et al. Macrophage-derived IL-1alpha promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell. Mol. Immunol. 15, 973–982 (2018).

    Article  CAS  Google Scholar 

  9. Jaeschke, H. Mechanisms of sterile inflammation in acetaminophen hepatotoxicity. Cell. Mol. Immunol. 15, 74–75 (2018).

    Article  CAS  Google Scholar 

  10. Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).

    Article  CAS  Google Scholar 

  11. Sica, A., Erreni, M., Allavena, P. & Porta, C. Macrophage polarization in pathology. Cell. Mol. Life Sci. 72, 4111–4126 (2015).

    Article  CAS  Google Scholar 

  12. Adams, D. H., Ju, C., Ramaiah, S. K., Uetrecht, J. & Jaeschke, H. Mechanisms of immune-mediated liver injury. Toxicol. Sci. 115, 307–321 (2010).

    Article  CAS  Google Scholar 

  13. Marra, F. & Tacke, F. Roles for chemokines in liver disease. Gastroenterology 147, 577–594 e571 (2014).

    Article  CAS  Google Scholar 

  14. Long, H. et al. Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-kappaB-mediated MMP-9 upregulation. Stem Cells 30, 2309–2319 (2012).

    Article  CAS  Google Scholar 

  15. Wang, S. W. et al. CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma. PLoS ONE 7, e35101 (2012).

    Article  CAS  Google Scholar 

  16. Kim, J. E. et al. LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression. Exp. Mol. Med. 40, 514–522 (2008).

    Article  CAS  Google Scholar 

  17. Marques, R. E., Guabiraba, R., Russo, R. C. & Teixeira, M. M. Targeting CCL5 in inflammation. Expert Opin. Ther. Targets 17, 1439–1460 (2013).

    Article  CAS  Google Scholar 

  18. Li, B. H., He, F. P., Yang, X., Chen, Y. W. & Fan, J. G. Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress. Transl. Res. 180, 103–117 e104 (2017).

    Article  CAS  Google Scholar 

  19. Berres, M. L. et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J. Clin. Invest 120, 4129–4140 (2010).

    Article  CAS  Google Scholar 

  20. Sadeghi, M. et al. Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma. Br. J. Cancer 113, 756–762 (2015).

    Article  CAS  Google Scholar 

  21. Mohs, A. et al. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J. Hepatol. 66, 743–753 (2017).

    Article  CAS  Google Scholar 

  22. Lee, C. M. et al. C-C chemokine ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury. Sci. Rep. 7, 3698 (2017).

    Article  Google Scholar 

  23. Wen, Y. et al. Metabolic modulation of acetaminophen-induced hepatotoxicity by osteopontin. Cell. Mol. Immunol. 16, 483–494 (2018).

  24. Triantafyllou, E. et al. MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure. Gut 67, 333–347 (2018).

    Article  CAS  Google Scholar 

  25. Bird, T. G. et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl. Med. 10, eaan1230 (2018).

  26. Bhushan, B. & Apte, U. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. Am. J. Pathol. 189, 719–729 (2019).

    Article  CAS  Google Scholar 

  27. Laskin, D. L. Macrophages and inflammatory mediators in chemical toxicity: a battle of forces. Chem. Res Toxicol. 22, 1376–1385 (2009).

    Article  CAS  Google Scholar 

  28. Choi, K. M. et al. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice. Gastroenterology 138, 2399–2409 (2010). 2409 e2391.

    Article  CAS  Google Scholar 

  29. Zhou, D. et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell. Signal. 26, 192–197 (2014).

    Article  CAS  Google Scholar 

  30. Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    Article  CAS  Google Scholar 

  31. Shi, J., Aisaki, K., Ikawa, Y. & Wake, K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am. J. Pathol. 153, 515–525 (1998).

    Article  CAS  Google Scholar 

  32. Ren, F. et al. Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism. Hepatology 54, 687–696 (2011).

    Article  CAS  Google Scholar 

  33. Woolbright, B. L. & Jaeschke, H. Sterile inflammation in acute liver injury: myth or mystery? Expert Rev. Gastroenterol. Hepatol. 9, 1027–1029 (2015).

    Article  CAS  Google Scholar 

  34. Perugorria, M. J. et al. Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut https://doi.org/10.1136/gutjnl-2017-314107 2018.

  35. Liew, P. X., Lee, W. Y. & Kubes, P. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 47, 752–765 e755 (2017).

    Article  CAS  Google Scholar 

  36. von Hundelshausen, P. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 105, 924–930 (2005).

    Article  Google Scholar 

  37. Mossanen, J. C. et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64, 1667–1682 (2016).

    Article  CAS  Google Scholar 

  38. Stutchfield, B. M. et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology 149, 1896–1909 e1814 (2015).

    Article  CAS  Google Scholar 

  39. Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    Article  CAS  Google Scholar 

  40. Ruytinx, P., Proost, P., Van Damme, J. & Struyf, S. Chemokine-induced macrophage polarization in inflammatory conditions. Front Immunol. 9, 1930 (2018).

    Article  Google Scholar 

  41. Mattison, H. A. et al. Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice. J. Neuroimmunol. 257, 110–115 (2013).

    Article  CAS  Google Scholar 

  42. Kim, D. et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 57, 1456–1465 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Zhang Yan at Shanghai Jiao Tong University for providing Ccl5−/− mice. This work was supported by the National Key Research and Development Program of China (2017YFC0908100 to Q.X.), the National Key Sci-Tech Special Project of China (2018ZX10723204-006-004 to X.K.), the National Natural Science Foundation of China (81873582 and 81670562 to X.K., 81670598 to Q.X., 31870905 and 31671453 to H.W.), and the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20171911 to X.K.).

Author information

Author notes

  1. These authors contributed equally: Meng Li, Xuehua Sun, Jie Zhao

Authors and Affiliations

  1. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Meng Li, Jie Zhao, Lei Xia, Jichang Li, Min Xu, Bingrui Wang, Han Guo, Chang Yu, Xiaoni Kong & Qiang Xia

  2. Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, Shugang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China

    Xuehua Sun, Yueqiu Gao & Xiaoni Kong

  3. Shanghai Key Laboratory of Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine & Health Science, Shanghai, China

    Hailong Wu

Authors
  1. Meng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuehua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jichang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bingrui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Han Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yueqiu Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hailong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaoni Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Qiang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.L. performed the experiments and wrote the manuscript. X.S., R.L., and Q.X. made the clinical diagnoses and collected the clinical samples. L.X., J.L., M.X., B.W., H.G., C.Y., J.Z., and Y.G. contributed to data collection and performed some experiments. H.W. critically edited the manuscript. X.K. and Q.X. designed and supervised the project and revised the manuscript for important content.

Corresponding authors

Correspondence to Hailong Wu, Xiaoni Kong or Qiang Xia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Sun, X., Zhao, J. et al. CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization. Cell Mol Immunol 17, 753–764 (2020). https://doi.org/10.1038/s41423-019-0279-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0279-0

Keywords

This article is cited by

Search

Advanced search

Quick links