Epithelial-immune cell crosstalk during injury and recovery in acute pancreatitis

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Acute pancreatitis (AP), an inflammatory disorder of the pancreas, is the most common gastrointestinal condition requiring hospitalization in the United States resulting in 275,000 hospital admissions annually. While many suffer only mild illness, some progress to severe AP characterized by multisystem organ failure and death. Intact immunity is vital for tissue protection and recovery from AP and data suggests that imbalance in pro and anti- inflammatory cytokines may underlie progression of disease. Evidence exists of communication between immune and epithelial cells in the pancreatic microenvironment but its role in AP remains understudied and further understating is needed to identify potential therapies aimed at enhancing organ repair. Interleukin-22 (IL22) has emerged as an important cytokine in host defense and tissue repair within the gastrointestinal tract and is often active in areas of inflammation. Previous studies and our own data have shown that IL22 signaling reduces tissue damage during AP by mechanisms related to autophagy. IL22 binding protein (IL22BP), a soluble neutralizing receptor, suppresses IL22 activity, and functions to maintain homeostasis. Only recently discovered, it is released from dendritic cells (DC) in response to retinoic acid stimulation and binds to IL22 with very high affinity. Induction of AP in mice using the cholecystokinin analogue cerulein results in a significant drop in IL22BP, suggesting it may serve as an adaptive response to tissue injury, enhancing protective IL22 signaling. Further supporting this is the markedly reduced pancreatic damage in transgenic mice lacking IL22BP given similar doses of cerulein. The goal of this proposal is to improve our understand of how IL22 signaling is regulated in AP through changes in expression of IL22BP. This is important as we have previously demonstrated that continued overexpression of IL22 is associated with malignant transformation in the pancreas. Our central hypothesis is that tissue injury in AP leads to an adaptive decrease in IL22BP which results from changes in RA metabolism. A return of IL22BP expression after recovery results in homeostatic suppression of IL22 signaling. We will test this hypothesis using transgenic mouse models and serum samples from a human AP cohort. Specific aim 1 will determine the mechanisms underlying the observed decreased tissue damage experienced by IL22BP-/- mice subjected to AP. We will explore changes in IL22 signaling, particularly related to autophagy and enhancement of genes involved in regeneration. Based on preliminary data that a key RA producing enzyme, ALDH1A1, is markedly reduced in AP, specific aim 2 will further characterize retinoic acid metabolism in the pancreas during injury and recovery. This will include in vivo studies using pharmacologic measures to inhibit RA anabolism with the goal of further reducing IL22BP production. Specific aim 3 will explore the crosstalk between acinar and immune cells and the role of autocrine and paracrine signaling of RA in DC production of IL22BP. Use of RA receptor blockade will be explored as a clinically relevant method to further reduce the adaptive decrease in IL22BP during AP, enhancing tissue recovery and preventing progression to severe AP.