TY - JOUR
T1 - A protective function of IL-22BP in ischemia reperfusion and acetaminophen-induced liver injury
AU - Kleinschmidt, Dorte
AU - Giannou, Anastasios D.
AU - McGee, Heather M.
AU - Kempski, Jan
AU - Steglich, Babett
AU - Huber, Francis Jessica
AU - Ernst, Thomas Michael
AU - Shiri, Ahmad Mustafa
AU - Wegscheid, Claudia
AU - Tasika, Elena
AU - Hubener, Peter
AU - Huber, Philipp
AU - Bedke, Tanja
AU - Steffens, Niklas
AU - Agalioti, Theodora
AU - Fuchs, Tobias
AU - Noll, Jill
AU - Lotter, Hannelore
AU - Tiegs, Gisa
AU - Lohse, Ansgar W.
AU - Axelrod, Jonathan H.
AU - Galun, Eithan
AU - Flavell, Richard A.
AU - Gagliani, Nicola
AU - Huber, Samuel
N1 - Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2017/12/15
Y1 - 2017/12/15
N2 - 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 3 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.
AB - 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 3 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.
UR - http://www.scopus.com/inward/record.url?scp=85038572939&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1700587
DO - 10.4049/jimmunol.1700587
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C2 - 29109123
AN - SCOPUS:85038572939
SN - 0022-1767
VL - 199
SP - 4078
EP - 4090
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -