Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / metabolism
  • Disease Progression
  • Fibrosis / metabolism
  • Fibrosis / pathology*
  • Humans
  • Inflammation
  • Interleukin-13 / metabolism
  • Interleukin-4 / metabolism
  • Interleukin-4 Receptor alpha Subunit / metabolism
  • Leukocytes / cytology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Stellate Cells / cytology
  • Pancreatitis, Chronic / metabolism*
  • Peptides / chemistry
  • Receptors, Cell Surface / metabolism
  • Signal Transduction

Substances

  • IL4 protein, human
  • IL4R protein, human
  • Il4ra protein, mouse
  • Interleukin-13
  • Interleukin-4 Receptor alpha Subunit
  • Peptides
  • Receptors, Cell Surface
  • Interleukin-4