Year: 2019
Type: article
Abstract: Macrophages play a critical role in pancreatitis progression and pancreas regeneration.Heparin-binding epidermal growth factor receptor-like growth factor derived from myeloid cells is not involved in the initiation of pancreatitis, but contributes to pancreas recovery after pancreatitis by promoting DNA damage repair. BACKGROUND & AIMS:Pancreatitis is a major cause of morbidity and mortality and is a risk factor for pancreatic tumorigenesis.Upon tissue damage, an inflammatory response, made up largely of macrophages, provides multiple growth factors that promote repair.Here, we examine the molecular pathways initiated by macrophages to promote pancreas recovery from pancreatitis.METHODS: To induce organ damage, mice were subjected to cerulein-induced experimental pancreatitis and analyzed at various times of recovery.CD11b-DTR mice were used to deplete myeloid cells.Hbegf f/f ;LysM-Cre mice were used to ablate myeloid cell-derived heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF).To ablate EGFR specifically during recovery, pancreatitis was induced in Egfr f/f ;Ptf1a FlpO/þ ;FSF-Rosa26 CAG-CreERT2 mice followed by tamoxifen treatment.RESULTS: Macrophages infiltrating the pancreas in experimental pancreatitis make high levels of HB-EGF.Both depletion of myeloid cells and ablation of myeloid cell HB-EGF delayed recovery from experimental pancreatitis, resulting from a decrease in cell proliferation and an increase in apoptosis.Mechanistically, ablation of myeloid cell HB-EGF impaired epithelial cell DNA repair, ultimately leading to cell death.Soluble HB-EGF induced EGFR nuclear translocation and methylation of histone H4, facilitating resolution of DNA damage in pancreatic acinar cells in vitro.Consistent with its role as the primary receptor of HB-EGF, in vivo ablation of EGFR from pancreatic epithelium during recovery from pancreatitis resulted in accumulation of DNA damage.CONCLUSIONS: By using novel conditional knockout mouse models, we determined that HB-EGF derived exclusively from myeloid cells induces epithelial cell proliferation and EGFRdependent DNA repair, facilitating pancreas healing after injury.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,000
Funders: Vanderbilt University, Northwestern University, Vanderbilt-Ingram Cancer Center, University of Michigan, Vanderbilt University Medical Center, National Institutes of Health, Diabetes Research and Training Center, Rogel Cancer Center, University of Michigan, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1240827852, G1404790370, G1457163447, G2019238319, G2112105340, G2940777275, Vanderbilt Mouse Metabolic Phenotyping Center, G3418398990, G3722609264, G3989539122, Vanderbilt Mouse Metabolic Phenotyping Center, G4513176822, G463003637, ADAM17 in pancreatic cancer and pancreatitis, G5914539713, G725763919, G79480885, G8239595131, Architecture and communication controlling the efficient generation of beta cells, G9000002043, G9000028576, G9000081609, G9000106052, G9000159340, G9000259993, G9000265070, G9000270405, Molecular and Cellular Basis for Digestive Diseases
OpenAlex ID: W2945828365