A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury

J Immunol. 2017 Dec 15;199(12):4078-4090. doi: 10.4049/jimmunol.1700587. Epub 2017 Nov 6.

Abstract

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 × Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression.

MeSH terms

  • Acetaminophen / toxicity*
  • Animals
  • Cell Movement
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / physiopathology*
  • Chemical and Drug Induced Liver Injury / prevention & control
  • Chemokine CXCL10 / antagonists & inhibitors
  • Chemokine CXCL10 / physiology
  • Constriction
  • Hepatectomy
  • Hepatocytes / metabolism
  • Interleukins / deficiency
  • Interleukins / metabolism
  • Ischemia / physiopathology
  • Liver / blood supply*
  • Liver / physiology
  • Liver Failure, Acute / etiology
  • Liver Failure, Acute / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / physiology
  • Receptors, Interleukin / deficiency
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / physiology*
  • Regeneration
  • Reperfusion Injury / physiopathology*
  • Reperfusion Injury / prevention & control

Substances

  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Interleukins
  • Receptors, Interleukin
  • interleukin-22 receptor
  • Acetaminophen
  • interleukin-22