Paneth cells-derived IL-17A and liver ischemia reperfusion injury

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Liver ischemia and reperfusion (IR) injury is a clinically significant problem during and after liver transplantation, hepatic resection and portal vein reconstruction surgery. Unfortunately, there is no therapy to prevent or treat hepatic IR injury. Furthermore, it is becoming increasingly clear that liver IR injury frequently results in significant extra-hepatic remote organ injury including kidney, intestinal and lung injury as well as a systemic inflammatory response syndrome and sepsis. In particular, the incidence of acute kidney injury after liver resection is extremely high and approaches ~50-80% after major hepatic resection or liver transplantation. Our previous studies implicate small intestinal crypt Paneth cells as the initiator of extra-hepatic remote organ injury after liver IR in mice. Furthermore, small intestinal Paneth cells are the predominant source of pro- inflammatory cytokine IL-17A required for generating hepatic and extra-hepatic injury in mice. However, for clinical translation of these studies leading to therapy, it is critical that we determine whether Paneth cell dysregulation and degranulation as well as Paneth cell release of IL-17A also occur after hepatic IR in human and nonhuman primate liver IR injury models. In this proposal, we will elucidate whether small intestinal Paneth cells dysregulate and release pro-inflammatory IL-17A after human and nonhuman primate liver IR injury and whether IL-17A neutralization attenuates liver injury as well as extra-hepatic organ injury after nonhuman primate IR. Exciting preliminary data suggest that cynomolgus monkey liver IR causes profound Paneth cell degranulation and Paneth cell IL-17A induction coupled with rapid kidney and small intestine injury. Furthermore, our preliminary data suggest that cynomolgus monkeys treated with IL-17A neutralizing antibody had markedly less hepatic IR injury as well as reduced post-operative AKI. Preliminary data also suggest that human small intestine Paneth cells degranulate after ischemic injury. Based on these preliminary findings, we hypothesize that hepatic IR injury leads to intestinal Paneth cell dysregulation/degranulation and Paneth cell- derived IL-17A induction leading to intestinal inflammation and apoptosis, subsequent exacerbation of hepatic injury and induction of acute kidney injury. We also hypothesize that IL-17A neutralization will attenuate hepatic, intestinal and kidney injury after liver IR in nonhuman primates. We will utilize both in vivo (highly translational cynomolgus monkey liver IR and human liver transplant studies) and in vitro (freshly isolated cynomolgus monkey and human Paneth cells) models to further elucidate the mechanisms and potential therapy for intestinal and renal injury after hepatic IR by testing the following three specific aims. Aim #1: To demonstrate remote organ injury and Paneth cell degranulation after liver IR injury. Aim #2: To demonstrate Paneth cell-mediated IL-17A release after liver IR injury. Aim #3: To develop therapies to reduce non-human primate liver IR injury induced hepatic and extra-hepatic organ injury.