Functional IKK/NF-kappa B signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis

Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-kappa B in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-kappa B in PSCs. Conditional deletion of NEMO (IKK gamma) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with caerulein, NEMO Delta Col1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with reduced latency period. Transcriptomic profiling shows that NEMO Delta Col1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSC Delta NEMO cells produce high levels of CCL24 ex vivo which contributes to eosinophil recruitment, as neutralization with a CCL24 antibody abolishes the transwell migration of eosinophils. Our findings uncover an unexpected immunomodulatory role specifically of NF-kappa B in PSCs during pancreatitis. A model of autoimmune pancreatitis is developed by blocking the activation of NF-kappa B in pancreatic stellate cells, via conditional deletion of NEMO (IKK gamma), which presents strong pancreatic inflammation with eosinophilia after the induction of chronic pancreatitis by repeated caerulein challenges.