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 -deficient mice and murine models of acute liver damage induced by ischemia reperfusion and-acetyl--aminophenol (acetaminophen) administration. We found that -deficient mice were more susceptible to acute liver damage in both models. We used × double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of by hepatocytes, and consequently increased infiltration of inflammatory CD11bLy6C monocytes into the liver in -deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced expression.

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