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

Idan Cohen,Martin Tomas,Charles A Dinarello,Mareike Wegner,Gerhard Mittler,Elena Vornov,Ron N Apte,Robert Schneider,Elisa Ferrando-May,Peleg Rider,Lydia Brondani,Cicerone Tudor,Marina Freudenberg

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.

Highlights

Due to a nuclear localization signal (NLS), the precursor form of IL-1α is found in the nucleus and can act as a dual function cytokine having an intracellular as well as extracellular mechanism of action[5], similar to HMGB1, IL-33 and IL-376
These reports suggest that cells that have been subjected to non-lethal stress can actively secrete the precursor form of IL-1α in addition to its passive release by necrotic cells
Since it had been reported that exposure to environmental factors that cause DNA damage may trigger precIL-1α secretion[4,10] and affect the progression and severity of inflammatory diseases[12,14,15,16,18,19], we examined the possibility that IL-1α could transduce signals from the nucleus to communicate chromatin damage to the surrounding tissue

Summary

Results and Discussion

Since it had been reported that exposure to environmental factors that cause DNA damage may trigger precIL-1α secretion[4,10] and affect the progression and severity of inflammatory diseases[12,14,15,16,18,19], we examined the possibility that IL-1α could transduce signals from the nucleus to communicate chromatin damage to the surrounding tissue. We found that TSA treatment increased the IL-1α nuclear signal and decreased the cytoplasmic signal over time, suggesting that HDACs could play a role in IL-1α sub-cellular localization (Fig. 3e and Supplementary Figure 3b). Images of cells expressing GFP IL-1α either non-treated (control) or treated with TSA (100 ng/ml) were collected every hour for 22 h and representative images for three time points (0, 11 and 22 hours) are shown (For averaged fluorescence intensities of nuclear/cytoplasmic ratios see Supplementary Figure 1b). Our results suggest that the classical cytokine IL-1α can act as an intracellular DNA damage sensor and report for cellular genotoxic stress This novel mechanism can contribute to downstream tissue repair and wound healing processes and may potentially effect development of autoimmunity or cancer. Uncontrolled IL-1 signaling may lead to acute pathogenesis, chronic diseases, autoimmunity and may promote tumorigenesis[12,18,19]

Methods

Author Contributions

Additional Information