Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.

Jing Xue,Michael H Hsieh,Aida Habtezion,Stephen J Pandol,Vishal Sharma,Ramachandran Murali,Ajay Chawla

doi:10.1038/ncomms8158

Abstract

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis, we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on IL-4 and IL-13 signaling 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 cross talk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

Highlights

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure
We identify a critical role for macrophages in pancreatic fibrosis and in turn pancreatic stellate cells (PSCs) as important inducers of macrophagealternative activation
Macrophages have been observed in close proximity to PSCs in human pancreatic fibrosis, and their presence observed in rat model of CP, not well defined, their potential role in CP has been suggested[11,12]

Summary

Introduction

Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression. We demonstrate that progression to CP is associated with alternative activation of macrophages and show an important role for the IL-4/IL-13 pathway in a crosstalk between macrophages and PSCs using in vivo and in vitro animal studies as well as ex vivo human primary cells. Blocking IL-4/IL-13 using a peptide antagonist we show a therapeutic effect in established experimental CP and proof-of-concept therapeutic ex vivo effect using human samples These studies are likely to offer potential benefit in a disease for which currently no active therapeutic agent exists and as such the disease is deemed progressive and irreversible

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