Acetaminophen, also called paracetamol outside the United States, is a commonly used painkiller, with over 50 million people in the United States taking the drug weekly. While paracetamol is safe at standard doses, overdose can cause acute liver failure, which leads to 30,000 patients being admitted to emergency care in the United States each year. There is only one approved antidote to overdoses, which becomes significantly less effective if its application is delayed by more than a few hours. This has incentivized research into identify new drug targets that could lead to additional treatment options.

Acetaminophen overdose triggers blood clotting and inflammation, contributing to liver injury. It also causes a decrease in cells called platelets circulating in the blood, which has been observed in both mice and humans. In mice, this occurs because platelets accumulate in the liver. Removing these excess cells appears to reduce the severity of the damage caused by acetaminophen, but it remains unclear how the drug triggers their accumulation in the liver. In 2018, researchers showed that a protein called Chi3l1 plays an important role in another form of liver damage. Shan et al. – including many of the researchers involved in the 2018 study – have examined whether the protein also contributes to acetaminophen damage in the liver.

Shan et al. showed that mice lacking the gene that codes for Chi3l1 developed less severe liver injury and had fewer platelets in the liver following acetaminophen overdose. They also found that human patients with acute liver failure due to acetaminophen had high levels of Chi3l1 and significant accumulation of platelets in the liver. To test whether damage could be prevented, Shan et al. used antibodies to neutralize Chi3l1 in mice after giving them an acetaminophen overdose. This reduced platelet accumulation in the liver and the associated damage.

These findings suggest that targeting Chi3l1 may be an effective strategy to prevent liver damage caused by acetaminophen overdose. Further research could help develop new treatments for acetaminophen-induced liver injury and perhaps other liver conditions.

Acute liver failure (ALF) is a life-threatening condition of massive hepatocyte injury and severe liver dysfunction that can result in multi-organ failure and death (Bernal and Wendon, 2013). Acetaminophen (APAP) overdose is the leading cause of ALF in Europe and North America and responsible for more cases of ALF than all other aetiologies combined (Bernal and Wendon, 2013; Jaeschke, 2015). It is estimated that each week, more than 50 million Americans use products containing APAP and approximately 30,000 patients are admitted to intensive care units every year due to APAP-induced liver injury (AILI) (Bernal and Wendon, 2013; Blieden et al., 2014). Although N-acetylcysteine (NAC) can prevent liver injury if given in time, there are still 30% of patients who do not respond to NAC (Fisher and Curry, 2019). Thus, identification of novel therapeutic targets and strategies is imperative.

APAP is metabolized predominantly by cytochrome P450 2E1 (CYP2E1) to a reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI causes mitochondrial dysfunction, lipid peroxidation, and eventually cell death (Hinson et al., 2004). The initial direct toxicity of APAP triggers the cascades of coagulation and inflammation, contributing to the progression and exacerbation of AILI (Hinson et al., 2004). In patients with APAP overdose, the clinical observations of thrombocytopenia, reduced plasma fibrinogen levels, elevated thrombin-antithrombin, and increased levels of pro-coagulation microparticles strongly suggest concurrent coagulopathy (Stravitz et al., 2013; Stravitz et al., 2016). Similarly, APAP challenge in mice causes a rapid activation of the coagulation cascade and significant deposition of fibrin(ogen) in the liver (Groeneveld et al., 2020; Sullivan et al., 2012; Sullivan et al., 2013). With regard to the role of platelets in AILI, it is reported that in mice APAP-induced thrombocytopenia correlates with the accumulation of platelets in the liver and that platelet depletion significantly attenuates AILI (Miyakawa et al., 2015). Two recent studies also demonstrate that persistent platelet accumulation in the liver delays tissue repair after AILI in mice (Chauhan et al., 2020; Groeneveld et al., 2020). These findings strongly indicate that hepatic platelet accumulation is a key mechanism contributing to AILI. However, little is known about the underlying molecular mechanism of APAP-induced hepatic platelet accumulation and whether targeting this process could attenuate AILI.

Chitinase 3-like-1 (Chi3l1) (YKL-40 in humans) is a chitinase-like soluble protein without chitinase activities (Lee et al., 2011). It is produced by multiple cell types, including macrophages, neutrophils, fibroblasts, synovial cells, endothelial cells, and tumor cells (Hakala et al., 1993; Kawada et al., 2007). Chi3l1 has been implicated in multiple biological processes including apoptosis, inflammation, oxidative stress, infection, and tumor metastasis (Lee et al., 2009). Elevated serum levels of Chi3l1 have been observed in various liver diseases, such as hepatic fibrosis, non-alcoholic fatty liver, alcoholic liver disease, and hepatocellular carcinoma (Kumagai et al., 2016; Lee et al., 2011; Nøjgaard et al., 2003; Wang et al., 2020). However, the biological function of Chi3l1 in liver disease is not clear. Our previous study revealed an important role of Chi3l1 in promoting intrahepatic coagulation in concanavalin A-induced hepatitis (Shan et al., 2018). Given the importance of intrahepatic coagulation in the mechanism of AILI, we wondered whether Chi3l1 is involved in platelets accumulation during AILI.

In the current study, we observed elevated levels of Chi3l1 in patients with APAP-induced ALF and in mice challenged with APAP overdose. Our data demonstrated a central role of Chi3l1 in APAP-induced hepatic platelet recruitment through CD44. Importantly, we found that targeting Chi3l1 by monoclonal antibodies could effectively inhibit platelet accumulation in the liver and markedly attenuate AILI.

The current study unveiled an important function of Chi3l1 in promoting platelet recruitment into the liver after APAP overdose, thereby playing a critical role in exacerbating APAP-induced coagulopathy and liver injury. Our data demonstrate that Chi3l1 signals through CD44 on Mɸs to upregulate podoplanin expression and promote platelet recruitment (Figure 7). Moreover, we report for the first time significant hepatic accumulation of platelets and marked upregulation of Chi3l1 in patients with ALF caused by APAP overdose. Importantly, we demonstrate that neutralizing Chi3l1 with mAbs can effectively inhibit hepatic platelet accumulation and mitigate liver injury caused by APAP, supporting the potential and feasibility of targeting Chi3l1 as a therapeutic strategy to treat AILI.

Figure 7

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The elevation of serum levels of Chi3l1 has been observed in various liver diseases (Kumagai et al., 2016; Lee et al., 2011; Nøjgaard et al., 2003; Wang et al., 2020), but studies of its involvement in liver diseases have only begun to emerge. There are several reports describing a role of Chi3l1 in models of chronic liver injuries caused by alcohol, CCl4, or high-fat diet (Higashiyama et al., 2019; Lee et al., 2019; Qiu et al., 2018; Zhang et al., 2021). However, the molecular and cellular mechanisms accounting for the involvement of Chi3l1 have yet to be defined. The present study unveils a function of Chi3l1 in promoting platelet recruitment to the liver during acute injury. We provide compelling data demonstrating that Chi3l1 acts through its receptor CD44 on Mɸs to recruit platelets, thereby contributing to AILI. Multiple receptors of Chi3l1 have been identified, including IL-13Rα2, CRTH2, TMEM219, and galectin-3 (Geng et al., 2018; He et al., 2013; Lee et al., 2016; Zhou et al., 2015; Zhou et al., 2018). The fact that Chi3l1 could bind to multiple receptors is consistent with a diverse involvement of Chi3l1 under different disease contexts. A recent study showed that Chi3l1 was upregulated during gastric cancer (GC) development and that through binding to CD44, it activated Erk, Akt, and β-catenin signaling, thereby enhancing GC metastasis (Geng et al., 2018). Our studies illustrated a novel role of Chi3l1/CD44 interaction in the recruitment of hepatic platelets and contribution to AILI. Our in vivo studies using Cd44^-/- mice and anti-CD44 antibody provide strong evidence that CD44 mediates the effects of Chi3l1. Our observation that Chi3l1 predominantly binds to CD44 on Mɸs, but not other CD44-expressing cells in the liver, suggests two possibilities which warrant further investigation. First, Chi3l1 may bind a specific isoform of CD44 that is uniquely expressed by Mɸs. Second, the Chi3l1-CD44 interaction requires binding of a co-receptor, which is expressed on Mɸs but not on other CD44-expressing cells in the liver.

We identified hepatic Mɸs as a key player in promoting platelet recruitment to the liver during AILI. Given the involvement of platelets in AILI, this finding would suggest that hepatic Mɸs also contribute to liver injury. The role of hepatic Mɸs in AILI has been a topic of debate and the current understanding is confined by the limitation of the methods used to deplete these cells (Campion et al., 2008; Fisher et al., 2013; Ju et al., 2002; Laskin et al., 1995; Michael et al., 1999). Several previous studies using CLDN to deplete Mɸs concluded that these cells play a protective role against AILI (Campion et al., 2008; Fisher et al., 2013; Ju et al., 2002). However, in those studies, Mɸ-depletion was confirmed by IHC staining of F4/80, which cannot distinguish KCs from IMs. Our laboratory and others had since developed a flow cytometric approach to detect and distinguish the two Mɸs populations. Using flow cytometry to monitor Mɸ-depletion, we found that the timing of CLDN treatment was critical. In the previously published reports, mice were treated with CLDN around 2 days before APAP challenge (Campion et al., 2008; Fisher et al., 2013; Ju et al., 2002). Using this treatment regimen, IMs became abundant prior to APAP treatment, even though KCs were depleted. Without this knowledge, previous studies attributed the worsened AILI to the depletion of KCs. However, the advancement of knowledge on the recruitment of IMs and their contribution to acute liver injury offers an alternative interpretation that the worsened AILI is due to IM accumulation (Chauhan et al., 2020; Holt et al., 2008; Mossanen et al., 2016; Zigmond et al., 2014). In the current study, we analyzed KCs and IMs in the liver at various time points after CLDN treatment to identify a new strategy to achieve more complete hepatic Mɸ-depletion. Our data demonstrated that when both Mɸs populations were absent at the time of APAP treatment, platelet recruitment was abrogated and AILI was significantly reduced. During the preparation of this manuscript, a study was published describing that IMs could recruit platelets (Chauhan et al., 2020). Together, these data suggest that hepatic Mɸs (both KCs and IMs) play a crucial role in promoting hepatic platelet accumulation, thereby contributing to AILI.

Our data suggest that platelet-derived Clec-2 interacts with podoplanin expressed on Mɸs, resulting in platelet recruitment to the liver during the early phase of AILI. The role of podoplanin/Clec-2 interaction in platelet recruitment and thromboinflammation has been indicated in multiple inflammatory and infectious conditions (Chauhan et al., 2020; Hitchcock et al., 2015; Kerrigan et al., 2012). Our data, for the first time, provide evidence that the podoplanin expression on Mɸs is regulated by the Chi3l1/CD44 axis. Future studies focusing on gaining molecular insight into such regulation are warranted. An increasing number of studies suggest that platelets play an important, but paradoxical role in liver injury. It has been proposed that they contribute to tissue damage during injury phase but promote tissue repair at later time points (Chauhan et al., 2016). However, two recent studies of AILI demonstrate that persistent platelet accumulation in the liver significantly delays liver repair. One study described a podoplanin/Clec-2 interaction between platelets and hepatic IMs during tissue repair and demonstrated a detrimental role of such interaction through blocking the recruitment of reparative neutrophils (Chauhan et al., 2020). Another study showed that AILI was associated with elevated plasma levels of von Willebrand factor, which prolonged hepatic platelet accumulation and delayed repair of APAP-injured liver in mice (Groeneveld et al., 2020). These studies together with our finding that platelets drive tissue damage during early stage of AILI suggest that platelets may be a therapeutic target to treat acute liver injury.

We observed hepatic platelet accumulation as early as 3 hr after APAP treatment in mice, prior to APAP-induced liver necrosis, indicating that platelets are likely to be the driver of AILI. Mitochondrial damage is a key event in APAP-induced cell necrosis, in which APAP triggers c-jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria, resulting in oxidant stress and the mitochondrial permeability transition pore opening (Saito et al., 2010). Others and our lab have reported that Chi3l1 can induce phosphorylation of JNK directly in either bronchial epithelial cells or LSEC line (Shan et al., 2018; Tang et al., 2013). However, whether Chi3l1 or Chi3l1-recruited platelets affects mitochondrial damage or mitochondrial JNK activation in hepatocytes warrants further investigation. During this study, we did compare the liver injuries among WT, and Chil1^-/-, Cd44^-/- mice in the recovery/regeneration stage of AILI (data not shown). Although ALT levels of WT mice were still slightly higher than both knockout strains of mice at 48 hr post-APAP, it is most likely due to high degrees of injury in WT at the initiation stage of AILI but not due to delayed repair. There were no differences in ALT levels at 72 hr post-APAP, again indicating that the Chi3l1/CD44 does not affect tissue recovery. Moreover, we compared ALT levels at 6 hr post-APAP and there were lower in Chil1^-/- and Cd44^-/- mice than WT mice (data not shown), which were consistent with the data shown at 24 hr, indicating that Chi3l1/CD44 axis is involved in the initiation and injury phases of AILI.

Our studies uncovered a previously unrecognized involvement of the Chi3l1/CD44 axis in AILI and provided insights into the mechanism by which Chi3l1/CD44 signaling promotes hepatic platelet accumulation and liver injury after APAP challenge. Taking our findings one -step further toward clinical application, we demonstrated the feasibility of targeting Chi3l1 by mAbs to attenuate AILI. There is an unmet need for developing treatments for AILI, as NAC is the only antidote at present. However, the efficacy of NAC declines rapidly when initiated more than a few hours after APAP overdose, long before patients are admitted to the clinic with symptoms of severe liver injury (Larson et al., 2005). Our studies provide strong support for the potential targeting of Chi3l1 as a novel therapeutic strategy to improve the clinical outcomes of AILI and perhaps other acute liver injury conditions.

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).

1. 1. An Z

   (2021) Baylor College of Medicine

   ID 4ea. Supplemental video 1, PBS treatment.

   https://bcm.box.com/s/15hmtryyrdl302mihrsm034ure87x4ea
2. 1. An Z

   (2021) Baylor College of Medicine

   ID tuljfmstvv4lvoksx16fkxkpirkekynz. Supplemental Video 2,APAP treatment.

   https://bcm.box.com/s/tuljfmstvv4lvoksx16fkxkpirkekynz

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Author details

1. Zhao Shan

   1. Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States
   2. Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "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

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

3. Constance Lynn Atkins

   Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States

   Contribution

   Data curation, Validation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Meng Wang

   Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Yankai Wen

   Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

   "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

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

7. Nicolas F Moreno

   Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

8. Dechun Feng

   Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, United States

   Contribution

   Resources, Writing - review and editing

   Competing interests

   No competing interests declared

9. Xun Gui

   Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

10. Ningyan Zhang

    Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Chun Geun Lee

    Molecular Microbiology and Immunology, Brown University, Providence, United States

    Contribution

    Resources

    Competing interests

    No competing interests declared

12. Jack A Elias

    1. Molecular Microbiology and Immunology, Brown University, Providence, United States
    2. Division of Medicine and Biological Sciences, Warren Alpert School of Medicine, Brown University, Providence, United States

    Contribution

    Resources

    Competing interests

    No competing interests declared

13. William M Lee

    Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Med School, Dallas, United States

    Contribution

    Resources, Writing - review and editing

    Competing interests

    No competing interests declared

14. Bin Gao

    Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, United States

    Contribution

    Conceptualization, Resources, Writing - review and editing

    Competing interests

    No competing interests declared

15. Fong Wilson Lam

    1. Division of Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, United States
    2. Center for Translation Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, United States

    Contribution

    Data curation, Investigation, Methodology

    Competing interests

    No competing interests declared

16. Zhiqiang An

    Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States

    Contribution

    Conceptualization, Resources, Writing - review and editing

    For correspondence

    zhiqiang.an@uth.tmc.edu

    Competing interests

    No competing interests declared

    "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

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Project administration, Writing - review and editing

    For correspondence

    Changqing.Ju@uth.tmc.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1640-7169

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