Regulation of exocrine pancreatic innate immunity via microbially induced IL-22

PROJECT SUMMARY Interleukin 22 (IL-22) is a microbe-induced cytokine that plays a crucial role in tissue homeostasis. The best- known pathway of IL-22 production requires the microbial stimulation of innate immune cells to release IL-23; IL- 23 then activates innate lymphoid cell type 3 (ILC3) and T helper 17 (Th17) cells to produce IL-22. IL-22 acts primarily on non-hematopoietic cells. It is crucial for regulating the production of anti-microbial proteins (AMPs), particularly the Reg gene family, in the intestine to control the microbiota or infections. Conversely, dysregulation of IL-22 is associated with intestinal pathologies. Interestingly, the pancreas is highly responsive to IL-22 and produces REG proteins, but it is not known whether pancreatic IL-22 levels or Reg gene transcription are regulated by the microbiota as is the case in the gut; this would be intriguing as the pancreas itself is a relatively sterile organ. Both elevated IL-22 and Reg levels are associated with poor prognosis in pancreatic diseases including pancreatitis and pancreatic ductal adenocarcinoma (PDAC), suggesting a pathogenic role for IL-22 in these disease contexts. However, the initial triggers of elevated pancreatic IL-22 have not been investigated, nor has a beneficial role for the high sensitivity of the pancreas to IL-22. Thus, this proposal will comprehensively establish the role of gut microbes in modulating pancreatic IL-22 and the consequences of this gut-to-pancreas axis on pancreatic health and disease. I hypothesize that gut microbes are crucial regulators of IL-22 in the pancreas, and while this is beneficial in promoting innate immune defenses to maintain pancreatic sterility, it becomes detrimental in the context of PDAC. Aim 1 will determine the impact of gut microbe induced IL-22 on pancreatic gene expression and the cellular mechanism underlying this phenomenon. In Aim 2, both the beneficial and detrimental roles of microbially induced IL-22 in the pancreas will be determined by modulating pancreatic IL-22 levels in mice challenged with intestinal infections in the context of IL-22 receptor deficiency or pancreatic cancer. This work will provide key insight into a previously undescribed mechanism of communication between the gut and pancreas via IL-22 with the goal of developing more targeted therapeutic interventions for pancreatic diseases. In addition to research, this fellowship will prioritize training and career development activities that will exceptionally prepare me to achieve my career goals of being a principal investigator at an academic institution. My training plan includes presenting my work both internally at the University of Chicago and at conferences, career development seminars, and teaching workshops. My research mentor, Dr. Daria Esterházy, along with the resources provided by the University of Chicago and the Committee on Immunology, will support and enrich my research training. This fellowship is an essential first step towards becoming a successful independent scientist and achieving my long-term career goals.