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

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 -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.

IL‐22 and IL‐22‐Binding Protein Are Associated With Development of and Mortality From Acute‐on‐Chronic Liver Failure

“…B). In this regard, STAT3 promotes the well‐described positive effect of IL‐22 on hepatocellular proliferation/survival, whereas STAT1 is rather a proinflammatory transcription factor inducing a large number of proinflammatory mediators and cytokines …”

“…However, high serum levels of IL‐22 have been associated with adverse outcomes in patients with alcoholic and nonalcoholic liver disease . Possible explanations for this phenomenon may include unwanted proinflammatory effects of IL‐22, which can augment Th17 immune responses, as well as insufficient biological activity of IL‐22 due to inhibitory mechanisms such as IL‐22BP …”

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

“…The role of IL-22 is currently being studied with mixed results in APAP hepatotoxicity. Knockout of IL-22 binding protein (IL-22BP) results in increased inflammation and increased liver injury in an IL-22/CXCL10 dependent manner [77]. However, pretreatment with IL-22 reduced injury through STAT3 activation [78].…”

Immunodysfunction in Acute-on-Chronic Liver Failure

“…Hence, high doses of IL-22 could be required for a therapeutic use of IL-22 in patients with ACLF. Furthermore, IL-22 also has proinflammatory functions that may adversely impact on the outcome of patients with severe liver diseases, and a recent study has revealed a protective role of IL-22BP in a murine model of acute liver failure [46]. Nevertheless, IL-22 appears to be a promising candidate to be investigated for the prevention and treatment of ACLF.…”

“…Of note, IL-22 signaling can be prevented by the soluble IL-22 binding protein (IL-22BP) [46]. IL-22 signaling is considered to be protective in chronic liver disease, as it strengthens the intestinal cellular barrier, promotes intestinal immune responses via induction of antimicrobial proteins, and promotes liver regeneration in vitro as well as in animal models [45].…”