IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary
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 interle...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2500061X |
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| author | Lei Sun Andrew G. Spiteri Brian D. Griffith Yaqing Zhang Marina Pasca Di Magliano Alberto C. Olivei Jake J. McGue Jacob Edwards Timothy L. Frankel |
| author_facet | Lei Sun Andrew G. Spiteri Brian D. Griffith Yaqing Zhang Marina Pasca Di Magliano Alberto C. Olivei Jake J. McGue Jacob Edwards Timothy L. Frankel |
| author_sort | Lei Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9ef6995684944896bb1a01a8f785dd5c |
| institution | OA Journals |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-9ef6995684944896bb1a01a8f785dd5c2025-08-20T02:05:43ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119810152010.1016/j.jcmgh.2025.101520IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummaryLei Sun0Andrew G. Spiteri1Brian D. Griffith2Yaqing Zhang3Marina Pasca Di Magliano4Alberto C. Olivei5Jake J. McGue6Jacob Edwards7Timothy L. Frankel8Department of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, MichiganDepartment of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan; Correspondence Address correspondence to: Timothy L. Frankel, MD, 1500 East Medical Center Drive, Ann Arbor, Michigan. 48109.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.http://www.sciencedirect.com/science/article/pii/S2352345X2500061XAcute PancreatitisChronic PancreatitisFibrosisIL-22IL-22BPInflammation |
| spellingShingle | Lei Sun Andrew G. Spiteri Brian D. Griffith Yaqing Zhang Marina Pasca Di Magliano Alberto C. Olivei Jake J. McGue Jacob Edwards Timothy L. Frankel IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary Cellular and Molecular Gastroenterology and Hepatology Acute Pancreatitis Chronic Pancreatitis Fibrosis IL-22 IL-22BP Inflammation |
| title | IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary |
| title_full | IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary |
| title_fullStr | IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary |
| title_full_unstemmed | IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary |
| title_short | IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic PancreatitisSummary |
| title_sort | il 22bp modulates injury in acute pancreatitis but delays tissue recovery in chronic pancreatitissummary |
| topic | Acute Pancreatitis Chronic Pancreatitis Fibrosis IL-22 IL-22BP Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2500061X |
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