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

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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.

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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

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.

Correspondence to Hailong Wu or Xiaoni Kong or Qiang Xia.

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The authors declare no competing interests.

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Keywords

  • CCL5
  • APAP
  • macrophage polarization
  • acute liver injury