Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice

J Hepatol. 2020 Apr;72(4):736-745. doi: 10.1016/j.jhep.2019.11.013. Epub 2019 Nov 29.


Background & aims: Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition.

Methods: To mimic ACLF conditions, we developed a severe liver injury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of a double dose of CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain the potential benefits of interleukin-22 (IL-22Fc) administration.

Results: This severe liver injury model recapitulated some of the key features of clinical ACLF, including acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality. Liver regeneration in this model was severely impaired because of a shift from the activation of the pro-regenerative IL-6/STAT3 pathway to the anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to the inability of Kupffer cells to produce IL-6; whereas the enhanced STAT1 activation was due to a strong innate immune response and subsequent production of IFN-γ. Compared to patients with DILI, patients with ACLF had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival in ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many antibacterial genes in a manner involving the anti-apoptotic protein BCL2.

Conclusions: Acute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from a pro-regenerative to an anti-regenerative pathway. IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment.

Lay summary: A mouse model combining chronic liver injury, acute hepatic insult, and bacterial infection recapitulates some of the key features of acute-on-chronic liver failure (ACLF) in patients. Both fibrosis and bacterial infection contribute to the impaired regenerative capacity of the liver in patients with ACLF. Herein, we show that IL-22Fc therapy improves ACLF by reprogramming impaired regenerative pathways and attenuating bacterial infection. Thus, it may have therapeutic potential for patients with ACLF.

Keywords: ACLF; Bacteria; IFN-γ; IL-6; STAT1; STAT3.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Acute-On-Chronic Liver Failure / blood*
  • Acute-On-Chronic Liver Failure / chemically induced
  • Acute-On-Chronic Liver Failure / drug therapy*
  • Acute-On-Chronic Liver Failure / microbiology
  • Adult
  • Animals
  • Carbon Tetrachloride / administration & dosage
  • Carbon Tetrachloride / adverse effects
  • Chemical and Drug Induced Liver Injury / blood*
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Chemical and Drug Induced Liver Injury / pathology
  • Disease Models, Animal
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Interleukins / administration & dosage*
  • Klebsiella Infections / drug therapy*
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae*
  • Kupffer Cells / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Regeneration / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Treatment Outcome


  • Interleukins
  • Carbon Tetrachloride
  • interleukin-22