IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity

Sci Rep. 2015 Oct 6;5:14756. doi: 10.1038/srep14756.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • DNA Damage / drug effects
  • DNA Damage / physiology*
  • DNA Damage / radiation effects
  • Histone Deacetylases / metabolism
  • Humans
  • Immunity, Innate / physiology*
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Skin / metabolism
  • Skin / radiation effects

Substances

  • IL1A protein, human
  • Interleukin-1alpha
  • Recombinant Proteins
  • Histone Deacetylases