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.

  • Letter to the Editor
  • Published:

IL-1α in acetaminophen toxicity: a sterile danger signal

Cellular & Molecular Immunology volume 15, pages 284–285 (2018)Cite this article

Much controversy surrounds the pathogenesis of acetaminophen-induced inflammation. Acetaminophen (APAP) is a well-studied xenobiotic that in high doses results in a deadly, yet preventable, form of liver failure. Although its effects are sudden and often irreversible, its mechanism is far from simple. In fact, at first glance, recent studies seem to refute each other. The field has been grappling with seemingly contradictory results driven mainly by often-generalized assumptions and different experimental systems. As always, the devil—or in this case, liver failure—is in the details. In this paper, Tang and colleagues identified macrophage-derived interleukin (IL)-1α as a mediator of sterile inflammation in a mouse model of APAP hepatotoxicity.1 IL-1α is an alarmin2 that unlike IL-1β, is constitutively expressed in many cells as a precursor. IL-1α precursor (pre-IL-1α) is active as a damage-associated molecular pattern (DAMP). After enzymatic cleavage, mature IL-1α can signal a more potent pro-inflammatory message.

First, to test the source of IL-1α, the authors directly probed hepatocytes, the most abundant cell type in the liver. They found that IL-1α is not derived from hepatocytes. Rather, macrophages were responsible for IL-1α production in the liver. Specifically, they found that 90% of IL-1α was derived from Kupffer cells, the resident liver macrophages (CD11bint/F4/80high). In an ex vivo co-culture model, this secretion was dependent on MyD88, an adaptor of both TLR4 and IL-1R1. This finding suggests that MyD88 plays a role in initial sensing of hepatocyte-derived DAMPs, such as HMGB1, and in potentiating autocrine IL-1 signaling through its receptor, IL-1R.

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

Figure 1

References

  1. Zhang C, Feng J, Du J, Zhuo Z, Yang S, Zhang W et al. Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol Immunol 2017 in press.

  2. Bertheloot D, Latz E . HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol 2016; 14: 43–64.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen C-J, Kono H, Golenbock D, Reed G, Akira S, Rock KL . Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 2007; 13: 851–856.

    Article  CAS  PubMed  Google Scholar 

  4. Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E et al. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol 2011; 187: 4835–4843.

    Article  CAS  PubMed  Google Scholar 

  5. Liu Z-X, Han D, Gunawan B, Kaplowitz N . Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 2006; 43: 1220–1230.

    Article  CAS  PubMed  Google Scholar 

  6. Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML et al. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2006; 216: 98–107.

    Article  CAS  PubMed  Google Scholar 

  7. Williams CD, Bajt ML, Farhood A, Jaeschke H . Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice. Liver Int 2010; 30: 1280–1292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lokuta MA, Nuzzi PA, Huttenlocher A . Calpain regulates neutrophil chemotaxis. Proc Natl Acad Sci USA 2003; 100: 4006–4011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tilg H, Moschen AR, Szabo G . Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2016; 64: 955–965.

    Article  CAS  PubMed  Google Scholar 

  10. Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 2009; 119: 305–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci USA 2012; 109: E3168–E3176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, MA, USA

    Arvin Iracheta-Vellve & Gyongyi Szabo

Authors
  1. Arvin Iracheta-Vellve
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gyongyi Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gyongyi Szabo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iracheta-Vellve, A., Szabo, G. IL-1α in acetaminophen toxicity: a sterile danger signal. Cell Mol Immunol 15, 284–285 (2018). https://doi.org/10.1038/cmi.2017.108

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2017.108

This article is cited by

Search

Advanced search

Quick links