title: IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.
abstract: Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1α acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1α knockout mice and show that IL-1α signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.
authors.forename: Idan
authors.initials: I
authors.lastname: Cohen
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 67404 Illkirch, France.|Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Cohen
authors.initials: C
authors.lastname: Idan
authors.forename: Peleg
authors.initials: P
authors.lastname: Rider
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
authors.forename: Rider
authors.initials: R
authors.lastname: Peleg
authors.forename: Elena
authors.initials: E
authors.lastname: Vornov
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
authors.forename: Voronov
authors.initials: V
authors.lastname: Elena
authors.forename: Martin
authors.initials: M
authors.lastname: Tomas
authors.affiliation: Bioimaging Center and Center for Applied Photonics, Department of Biology and Department of Physics, University of Konstanz, Konstanz, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Martin
authors.forename: Cicerone
authors.initials: C
authors.lastname: Tudor
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Tudor
authors.initials: T
authors.lastname: Cicerone
authors.forename: Mareike
authors.initials: M
authors.lastname: Wegner
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.|Department of Dermatology, Medical Center and Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Wegner
authors.initials: W
authors.lastname: Mareike
authors.forename: Lydia
authors.initials: L
authors.lastname: Brondani
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Brondani
authors.initials: B
authors.lastname: Lydia
authors.forename: Marina
authors.initials: M
authors.lastname: Freudenberg
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.|BIOSS, Faculty of Biology III, University of Freiburg, Freiburg, Germany.
authors.forename: Freudenberg
authors.initials: F
authors.lastname: Marina
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mittler
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Mittler
authors.initials: M
authors.lastname: Gerhard
authors.forename: Elisa
authors.initials: E
authors.lastname: Ferrando-May
authors.affiliation: Bioimaging Center and Center for Applied Photonics, Department of Biology and Department of Physics, University of Konstanz, Konstanz, Germany.
authors.forename: Ferrando-May
authors.initials: FM
authors.lastname: Elisa
authors.affiliation: University of Colorado Denver, Aurora, CO USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
authors.forename: Apte N
authors.initials: AN
authors.lastname: Ron
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
authors.forename: Schneider
authors.initials: S
authors.lastname: Robert
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000528:radiation effects
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; D011994:Recombinant Proteins; D006655:Histone Deacetylases