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Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis

Author

Listed:
  • Jing Xue

    (Stanford University School of Medicine)

  • Vishal Sharma

    (Stanford University School of Medicine)

  • Michael H. Hsieh

    (Stanford University School of Medicine, Stanford University
    Present address: Department of Urology, the George Washington University 20037, and Children's National Health System, Washington, District of Columbia 20010, USA and the Biomedical Research Institute, Rockville, Maryland 20852, USA)

  • 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)

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.

Suggested Citation

  • Jing Xue & Vishal Sharma & Michael H. Hsieh & Ajay Chawla & Ramachandran Murali & Stephen J. Pandol & Aida Habtezion, 2015. "Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8158
    DOI: 10.1038/ncomms8158
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    Cited by:

    1. Juliane Glaubitz & Anika Wilden & Janine Golchert & Georg Homuth & Uwe Völker & Barbara M. Bröker & Thomas Thiele & Markus M. Lerch & Julia Mayerle & Ali A. Aghdassi & Frank U. Weiss & Matthias Sendle, 2022. "In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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