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

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.

Reviewing Editor

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

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.

Version history

  1. Received: March 19, 2021
  2. Accepted: June 2, 2021
  3. Accepted Manuscript published: June 10, 2021 (version 1)
  4. Version of Record published: June 25, 2021 (version 2)

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.

Metrics

  • 1,300
    Page views
  • 281
    Downloads
  • 19
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  17. Cynthia Ju
(2021)
Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment
eLife 10:e68571.
https://doi.org/10.7554/eLife.68571

Share this article

https://doi.org/10.7554/eLife.68571

Further reading

    1. Biochemistry and Chemical Biology
    2. Medicine
    Giulia Leanza, Francesca Cannata ... Nicola Napoli
    Research Article

    Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.

    1. Medicine
    Valentina Daponte, Katrin Henke, Hicham Drissi
    Review Article

    Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While the influence of osteoblasts on osteoclast differentiation is well established, the reciprocal regulation of osteoblasts by osteoclasts has long remained enigmatic. In the past few years, a fascinating new role for osteoclasts has been unveiled in promoting bone formation and facilitating osteoblast migration to the remodeling sites through a number of different mechanisms, including the release of factors from the bone matrix following bone resorption and direct cell–cell interactions. Additionally, considerable evidence has shown that osteoclasts can secrete coupling factors known as clastokines, emphasizing the crucial role of these cells in maintaining bone homeostasis. Due to their osteoprotective function, clastokines hold great promise as potential therapeutic targets for bone diseases. However, despite long-standing work to uncover new clastokines and their effect in vivo, more substantial efforts are still required to decipher the mechanisms and pathways behind their activity in order to translate them into therapies. This comprehensive review provides insights into our evolving understanding of the osteoclast function, highlights the significance of clastokines in bone remodeling, and explores their potential as treatments for bone diseases suggesting future directions for the field.