The accurate replication and repair of DNA is central to organismal survival. This process is challenged by the many factors that can change genetic information such as replication errors and direct damage to the DNA molecule by chemical and physical agents. DNA damage can also result from microorganism invasion as an integral step of their life cycle or as collateral damage from host defense mechanisms against pathogens. Here we review the complex crosstalk of DNA damage response and immune response pathways that might be evolutionarily connected and argue that DNA damage response pathways can be explored therapeutically to induce disease tolerance through the activation of tissue damage control processes. Such approach may constitute the missing pillar in the treatment of critical illnesses caused by multiple organ failure, such as sepsis and septic shock.
DNA damage responses modulate inflammation-driven conditions. DNA damage response pathways are deeply interconnected with immune and inflammatory responses. Shared molecular circuits demonstrate their cross-regulation and open the possibility of the exploration of their connections for the development of novel therapeutic strategies. These might offer important advantages in the treatment of severe inflammatory conditions, including sepsis, by triggering disease tolerance.