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PMID: 25981357 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.

Nature communications ·Vol. 6 ·2015-05-18 ·Pages 7158

Xue J, Sharma V, Hsieh MH, Chawla A, Murali R, Pandol SJ, Habtezion A

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.

MeSH Terms
Animals Carcinoma, Pancreatic Ductal/metabolism Disease Progression Fibrosis/metabolism,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,pathology Pancreatic Neoplasms/metabolism Pancreatic Stellate Cells/cytology Pancreatitis, Chronic/metabolism Peptides/chemistry Receptors, Cell Surface/metabolism Signal Transduction
Chemicals
IL4 protein, human IL4R protein, human Il4ra protein, mouse Interleukin-13 Interleukin-4 Receptor alpha Subunit Peptides Receptors, Cell Surface Interleukin-4
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Xue Jing
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Sharma Vishal
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Hsieh Michael H
Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
Chawla Ajay
Department of Physiology and Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
Murali Ramachandran
Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Pandol Stephen J
Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Habtezion Aida
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms8158
Published
2015-05-18
Epub
2015-00-18
Pages
7158
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4632846
Subset
IM
Grants
NIDDK NIH HHS · R01 DK092421 · United States
NCI NIH HHS · P01CA163200 · United States
NIDDK NIH HHS · P30 DK063720 · United States
NCI NIH HHS · P01 CA163200 · United States
NIAAA NIH HHS · P50 AA11999 · United States
NIDDK NIH HHS · DK092421 · United States
BLRD VA · I01 BX001484 · United States
NIDDK NIH HHS · P01 DK098108 · United States
NIAAA NIH HHS · P50 AA011999 · United States
NIGMS NIH HHS · T32 GM008111 · United States
Corrections
CommentIn
PMID: 26035679
External Links
PubMed source DOI: 10.1038/ncomms8158 PMC Full Text View journal details
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