biostudies-literatureCohen INIAID NIH HHSNCI NIH HHSNIAMS NIH HHS14756https://www.ebi.ac.uk/biostudies/studies/S-EPMC4593953biostudies-literatureUnknown5Environmental 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-1?). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1? 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-1? acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1? knockout mice and show that IL-1? 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.Scientific reportsIL-1? is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.PMC4593953R01 AR045584R01 AI015614CA-04-6934AI-15614R56 AI015614AR-45584Ron ANIdan CTudor CGerhard MMittler GBrondani LRider PLydia BElisa FMMartin TCicerone TVornov EPeleg RRobert SSchneider RFreudenberg MTomas MMareike WWegner MFerrando-May EApte RNCohen IElena VMarina FDinarello CAfalseIL-1? is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.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-1?). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1? 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-1? acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1? knockout mice and show that IL-1? 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.2015-01-01T00:00:00Z2015 Oct2020-11-19T14:34:51Z2019-03-27T01:59:32ZS-EPMC45939532643990210.1038/srep14756