IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity
SourceScientific Reports, 5, (2015), article 14756
Article / Letter to editor
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SubjectRadboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
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-1alpha). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1alpha 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-1alpha acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1alpha knockout mice and show that IL-1alpha 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.
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