Paneth cell-derived interleukin-17A causes multiorgan dysfunction after hepatic ischemia and reperfusion injury

Abstract

Hepatic ischemia and reperfusion (IR) injury is a major clinical problem that leads to frequent extrahepatic complications including intestinal dysfunction and acute kidney injury (AKI). In this study we aimed to determine the mechanisms of hepatic IR-induced extrahepatic organ dysfunction. Mice subjected to 60 minutes 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 interleukin-17A (IL-17A) levels in portal vein plasma and small intestine. We also detected increased levels of IL-17A messenger RNA (mRNA) and protein in Paneth cells after hepatic IR with laser capture dissection. 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 infusion of wildtype splenocytes failed to exacerbate liver and kidney injury in IL-17A-deficient mice after hepatic IR. Depletion of Paneth cell numbers by pharmacological (with dithizone) or genetic intervention (SOX9 flox/flox Villin cre1/2 mice) significantly attenuated intestinal, hepatic, and renal injury following liver IR. Finally, depletion of Paneth cell numbers significantly decreased small intestinal IL-17A release and plasma IL-17A levels after liver IR. Conclusion: Taken together, the results show that Paneth cell-derived IL-17A plays a critical role in hepatic IR injury and extrahepatic organ dysfunction. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from hepatic IR. (HEPATOLOGY 2011;53:1662-1675

Amelioration of hypoxia and LPS-induced intestinal epithelial barrier dysfunction by emodin through the suppression of the NF-κB and HIF-1α signaling pathways

“…Both animal and human studies have indicated that hypoxia elicits tissue inflammation, so-called hypoxia-elicited inflammation (57)(58)(59)(60). Similarly, during inflammation, such as inflammatory bowel disease, the inflammatory organ becomes ischemic, so-called inflammatory hypoxia or inflammation-associated tissue hypoxia (61)(62)(63)(64).…”

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

“…CD4+ T cells include not only Th1 and Th2 cells but also T helper 17 cells (Th17), Tregs and T follicular helper cells (Tfh). Previous studies have also shown that RAR-related orphan receptor gamma (RORγ)+IL-17+ neutrophils and IL-17A-producing natural killer cells play critical roles in a modified model of liver IRI, which occurred in RAG-deficient hosts [10]. Another study demonstrated that ex vivo-induced Treg cells could protect livers from IRI by inhibiting the activation of Kupffer cells in a liver partial warm ischemia model [11].…”

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

“…I n liver transplantation, organ exposure to ischemia and reperfusion during the transplantation process often leads to poor graft function; moreover, it may cause inflammatory activation in the intestine leading to multiorgan failure (1,2). Unfortunately, a lack of transplantable human livers has led to the usage of "marginal" organs at high-risk for severe ischemia reperfusion injury (IRI) (3).…”