title: Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism.
abstract: The DNA damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity.
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Geiger-Maor
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Guedj
authors.affiliation: Hadassah Human Embryonic Stem Cell Research Center, Goldyne Savad Institute of Gene Therapy, Hadassah- Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Even-Ram
authors.affiliation: Genomic Data Analysis Unit of the Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Smith
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. rjacob444@gmail.com.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rachmilewitz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000276:immunology*; D059766:DNA End-Joining Repair / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D066257:Heparin-binding EGF-like Growth Factor / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D066246:ErbB Receptors