title: Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Department of Physiology and Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
authors.affiliation: Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Habtezion
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000166:cytology; D050500:Pancreatitis, Chronic / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508598:IL4 protein, human; C504000:IL4R protein, human; C504002:Il4ra protein, mouse; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; D010455:Peptides; D011956:Receptors, Cell Surface; D015847:Interleukin-4