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Nat Commun. 2015 May 18;6:7158. doi: 10.1038/ncomms8158.

Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.

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Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
Department of Physiology and Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.


Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

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