Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis

Jing Xue, Vishal Sharma, Michael H. Hsieh, Ajay Chawla, Ramachandran Murali, Stephen J. Pandol and Aida Habtezion ()
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Jing Xue: Stanford University School of Medicine
Vishal Sharma: Stanford University School of Medicine
Michael H. Hsieh: Stanford University School of Medicine, Stanford University
Ajay Chawla: Cardiovascular Research Institute, University of California
Ramachandran Murali: Cedars-Sinai Medical Center
Stephen J. Pandol: Cedars-Sinai Medical Center
Aida Habtezion: Stanford University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8158

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