A protective function of IL-22BP in acute liver injury

Acute liver injury is a critical life-threatening event. Common causes are infections, intoxication, and ischemic conditions. The cytokine Interleukin 22 (IL-22) has been implicated in this process. However, the role of IL-22 during acute liver damage is controversial, since both protective and pathogenic properties have been reported. IL-22 binding protein (IL-22BP, IL-22Ra2), a soluble endogenous inhibitor of IL-22, is able to regulate IL-22 activity, and thus might explain some of the controversial findings. Since the role of IL-22BP in liver injury is unknown, we used Il22bp deficient mice and mouse models for acute liver damage to address this point. We found that Il22bp deficient mice were more susceptible to ischemia- and acetaminophen- induced liver damage. Deficiency of Il22bp caused increased hepatic damage and delayed liver regeneration. Using an unbiased approach, we found that IL-22, if uncontrolled in Il22bp deficient mice, induced Cxcl10 expression by hepatocytes, thereby recruiting inflammatory CD11b+Ly6C+ monocytes into the liver upon liver damage. Accordingly, neutralization of Cxcl10 reversed the increased disease susceptibility of Il22bp deficient mice. In conclusion, our data suggest dual functions of IL-22 in acute liver damage, and highlight the need to control IL-22 activity via IL-22BP. Overall design: RNA sequencing of RNA isolated from liver tissue from mice that underwent liver reperfusion treatment (IR) or sham surgery, in triplicate for three genotypes (Wt, Il22-/- and Il22bp-/-).

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Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod JH, Galun E, Flavell RA, Gagliani N, Huber S