IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic Pancreatitis

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BACKGROUND & AIMS: In acute pancreatitis, interleukin (IL)-22 signaling is increased, whereas overall expression of the cytokine paradoxically drops, suggesting an additional level of control. Here, we investigate the regulation of IL-22 signaling by its soluble neutralizing receptor interleukin-22 binding protein (IL-22BP) in the context of both acute and chronic pancreatitis. METHODS: Cerulein was used to induce acute and chronic pancreatitis in both wild-type mice and IL-22BP knockout mice. Histology, multiplex immunofluorescence and flow cytometry were performed to compare differences in tissue injury, recovery, fibrosis, and inflammation at various times of recovery. RESULTS: Loss of IL-22BP resulted in increased canonical IL-22 signaling and the expression of the anti-autophagy protein Bcl-XL. This was associated with decreased severity of acute pancreatitis, as evidenced by lower serum amylase and tissue injury. In chronic pancreatitis, IL-22BP expression was induced in the inflammatory and recovery phases and genetic deletion resulted in unchecked IL-22 signaling, as demonstrated by persistent p-Stat3 signaling and proliferation of both epithelial cells and fibroblasts. Loss of IL-22BP increased myeloid cell infiltration, which persisted throughout recovery. Mechanistically, IL-22 activity forced persistent acinar to ductal metaplasia and delayed tissue recovery. CONCLUSIONS: IL-22BP plays an important role in modulating IL-22 activity during tissue injury and recovery after pancreatitis. Loss of IL-22BP attenuated acute pancreatitis but promoted chronic fibrosis and inflammation through uncontrolled IL-22 signaling and subsequent deleterious effects on epithelial cells, fibroblasts, and immune infiltration.

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