Functional IKK/NF-κB 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-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Its function in PSCs during chronic pancreatitis has not been investigated. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO(IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with experimental chronic pancreatitis, NEMOΔCol1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with extremely reduced latency period. These mice fail to recover even 18 weeks after the induction of pancreatitis but show sustained fibrosis and elevated eosinophil infiltration. Transcriptomic profiling shows that NEMOΔCol1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSCΔNEMO cells have higher fibrogenic activities (upregulated Col1a1 and Col3a1) and produce high levels of eotaxin-2 (CCL24) which contributes to eosinophil recruitment. Corticosteroid treatment strongly attenuates the autoimmune phenotype in NEMOΔCol1a2 mice. Our findings uncover an important and unexpected immunomodulatory role specifically of NF-κB in PSCs and its deregulation may be a trigger of autoimmune pancreatitis.