Critical role of Paneth cell‐derived IL‐17A in hepatic ischemia and reperfusion injury

Abstract

Hepatic ischemia and reperfusion (IR) injury is a major clinical problem with frequent extra‐hepatic complications including intestinal dysfunction and acute kidney injury (AKI). We aimed to determine the mechanisms of hepatic IR‐induced systemic complications. Mice subjected to 60 min of hepatic IR not only developed severe hepatic injury but also developed significant AKI and small intestinal injury. Hepatic IR induced small intestinal Paneth cell degranulation and increased IL‐17A levels in portal plasma and small intestine. IL‐17A neutralizing antibody treatment or genetic deletion of either IL‐17A or IL‐17A receptors significantly protected against hepatic IR‐induced acute liver, kidney and intestinal injury. Leukocyte IL‐17A does not contribute to organ injury as wild type splenocytes infused into IL‐17A deficient failed to exacerbate liver and kidney injury after hepatic IR. Laser capture micro‐dissection of Paneth cells showed significant IL‐17A mRNA induction after hepatic IR. Finally, wild type mice treated with dithizone to deplete Paneth cells or Paneth cell deficient (Sox9flox/flox;VilCre) mice were protected against hepatic, renal and intestinal injury following liver IR. Taken together, the results show that Paneth cell derived IL‐17A plays a critical role in hepatic IR injury and extra‐hepatic organ dysfunction. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from hepatic IR.Supported by Department of Anesthesiology, Columbia University.