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Cell Mol Gastroenterol Hepatol. 2019 May 21. pii: S2352-345X(19)30068-2. doi: 10.1016/j.jcmgh.2019.05.006. [Epub ahead of print]

Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis.

Author information

1
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
2
Xiangya School of Medicine, Central South University, China.
3
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
4
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
5
Department of Molecular Physiology and Biophysics, Center for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee.
6
Department of Surgery, University of Michigan, Ann Arbor, Michigan; Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
7
Department of Surgery, University of Michigan, Ann Arbor, Michigan.
8
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Electronic address: howcraw@umich.edu.

Abstract

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. Hbegff/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 Egfrf/f;Ptf1aFlpO/+;FSF-Rosa26CAG-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 EGFR-dependent DNA repair, facilitating pancreas healing after injury.

KEYWORDS:

DNA Damage; EGFR; Inflammation; Macrophages

PMID:
31125624
DOI:
10.1016/j.jcmgh.2019.05.006
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