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Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment

  1. Zhao Shan
  2. Leike Li
  3. Constance Lynn Atkins
  4. Meng Wang
  5. Yankai Wen
  6. Jongmin Jeong
  7. Nicolas F Moreno
  8. Dechun Feng
  9. Xun Gui
  10. Ningyan Zhang
  11. Chun Geun Lee
  12. Jack A Elias
  13. William M Lee
  14. Bin Gao
  15. Fong Wilson Lam
  16. Zhiqiang An  Is a corresponding author
  17. Cynthia Ju  Is a corresponding author
  1. Yunnan University, China
  2. UTHealth McGovern Medical School, United States
  3. National Institute on Alcohol Abuse and Alcoholism, United States
  4. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, United States
  5. Brown University, United States
  6. University of Texas Southwestern Med School, United States
  7. Baylor College of Medicine, United States
  8. Brown Foundation Institute of Molecular Medicine, United States
Research Article
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Cite this article as: eLife 2021;10:e68571 doi: 10.7554/eLife.68571

Abstract

Background: Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI.

Methods: Mice were fasted overnight before i.p. injected with APAP at a dose of 210 mg/kg for male mice and 325 mg/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of α-Chi3l1 on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed.

Results: The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chil1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of Cd44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chil1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chil1-/- mice, but not in Cd44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI.

Conclusions: we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.

Funding: ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042-20030616). C.J. received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work was supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Data availability

Intravital microscopy videos can be reached via the following links: https://bcm.box.com/s/15hmtryyrdl302mihrsm034ure87x4ea (Supplemental video 1, PBS treatment) and https://bcm.box.com/s/tuljfmstvv4lvoksx16fkxkpirkekynz (Supplemental Video 2, APAP treatment)(n=6-7 mice/group, 4-15 videos/mouse).

Article and author information

Author details

  1. Zhao Shan

    School of Life Science, Yunnan University, Kunming, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5064-1023
  2. Leike Li

    Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Constance Lynn Atkins

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Meng Wang

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yankai Wen

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8144-1515
  6. Jongmin Jeong

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicolas F Moreno

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Dechun Feng

    Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Xun Gui

    Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ningyan Zhang

    Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Chun Geun Lee

    Department of Molecular Microbiology and Immunology, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jack A Elias

    Department of Molecular Microbiology and Immunology, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. William M Lee

    Department of Internal Medicine, University of Texas Southwestern Med School, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Bin Gao

    Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Fong Wilson Lam

    Division of Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Zhiqiang An

    University of Texas Health Science Center at Houston, Brown Foundation Institute of Molecular Medicine, Houston, United States
    For correspondence
    zhiqiang.an@uth.tmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9309-2335
  17. Cynthia Ju

    Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
    For correspondence
    Changqing.Ju@uth.tmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1640-7169

Funding

National Natural Science Foundation of China (32071129)

  • Zhao Shan

National Institutes of Health (GM123261)

  • Fong Wilson Lam

National Institutes of Health (DK122708,DK109574,DK121330,and DK122796)

  • Cynthia Ju

National Institute of Diabetes and Digestive and Kidney Diseases (DK 058369)

  • William M Lee

Cancer Prevention and Research Institute of Texas (RP150551 and RP190561)

  • Zhiqiang An

Welch Foundation (AU-0042-20030616)

  • Zhiqiang An

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal studies described have been approved by the UTHealth Institutional Animal Care and Use Committee (IACUC AWC-20-0074)

Human subjects: Serum samples from patients diagnosed with APAP-induced liver failure on day 1 of admission were obtained from the biobank of the Acute Liver Failure Study Group (ALFSG) at UT Southwestern Medical Center, Dallas, TX, USA. The study was designed and carried out in accordance with the principles of ALFSG and approved by the Ethics Committee of ALFSG (HSC-MC-19-0084). Formalin-fixed, paraffin-embedded human liver biopsies from patients diagnosed with APAP-induced liver failure were obtained from the National Institutes of Health-funded Liver Tissue Cell Distribution System at the University of Minnesota, which was funded by NIH contract # HHSN276201200017C.

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Publication history

  1. Received: March 19, 2021
  2. Accepted: June 2, 2021
  3. Accepted Manuscript published: June 10, 2021 (version 1)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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