Mini reviewDNA damage talks to inflammation

- Interleukin-1 cytokines, Interleukin-1alpha (IL-1α) and Interleukin-1beta (IL-1β) bind the same IL-1 receptor (IL-1R) but exhibit major differences in their biology, secretion mechanisms, and intracellular localization.
- IL-1α can directly and actively sense cellular genotoxic stress and signal to the environment when released from live cells undergoing physiological stress.
- The cytokine or alarmin activity of IL-1α is linked and regulated by its chromatin binding properties.
- This activity brings a novel immunological concept and add a new layer to the classical “Danger model” by showing that dual function cytokines as danger-associated molecular pattern are not only passively released from dying cells to initiate danger signaling.
- Chronic danger signaling as central initiation step of sterile inflammation in response to non-lethal stress might be responsible for many of the systemic low grade sterile inflammation that can be seen in many diseases and should be targeted for inhibition as a novel therapeutic approach.

Interleukin-1 alpha (IL-1α) and beta (IL-1β) are pleiotropic cytokines affecting multiple cells and regulating many immune and inflammatory responses. The recent finding that nuclear IL-1α is recruited to sites of DNA damage, and its ability to actively sense and report genotoxic stress to the surrounding tissue, dramatically alters the way we view IL-1 biology. This discovery add a new face to the classical “danger theory” and show that danger signaling is not strictly limited to passive release or dying cells. Most importantly, as now physiological stresses are linked to the release or secretion of IL-1α, chronic danger signaling and the alarmin inhibition should be considered as a new therapeutic approach for many diseases that are characterized by ongoing DNA damage, stress signaling and inflammation.