Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

Abstract

Summary Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

Tissue damage control in disease tolerance

“…This notion is in keeping with the growing recognition that a number of cancers are directly or indirectly associated with history of infection 60 . Pharmacologic targeting of DNA-damage-responses regulated by the Ser/Thr protein kinase ataxia telangiectasia-mutated (ATM) 61 provides a robust protective response against severe sepsis elicited by polymicrobial infection in mice 62 (Fig. 4).…”

“…This protective effect acts via a mechanism that does not interfere with host pathogen load, conferring tissue damage control and disease tolerance to sepsis 62 . More specifically, DNA-damage-responses appear to act predominately at the level of the lung epithelium to confer tissue damage control, arguing for a central pathologic role exerted by damage to the lung epithelium in the pathogenesis of severe sepsis 62 . Whether ATM and/or other regulators of DNA damage-responses act under pathophysiologic conditions to confer tissue damage control during different types of infection is likely, but this remains to be established (Fig. …”

“…Autophagy and its manipulation by pathogens modulates host resistance mechanisms 68 . More recently autophagy has also been shown to modulate tissue damage control and disease tolerance, as illustrated in the context of polymicrobial infection in mice 62 . Briefly, pharmacologic induction of DNA-damage response by anthracyclines, a group of chemotherapeutic agents that activate DNA damage-responses involving ATM, provides robust protection against severe sepsis in mice 62 .…”

“…More recently autophagy has also been shown to modulate tissue damage control and disease tolerance, as illustrated in the context of polymicrobial infection in mice 62 . Briefly, pharmacologic induction of DNA-damage response by anthracyclines, a group of chemotherapeutic agents that activate DNA damage-responses involving ATM, provides robust protection against severe sepsis in mice 62 . This salutary effect acts via a mechanism involving two components of the autophagy damage response, namely the autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) and the autophagy-related protein 7 (Atg7) 62 .…”

“…Briefly, pharmacologic induction of DNA-damage response by anthracyclines, a group of chemotherapeutic agents that activate DNA damage-responses involving ATM, provides robust protection against severe sepsis in mice 62 . This salutary effect acts via a mechanism involving two components of the autophagy damage response, namely the autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) and the autophagy-related protein 7 (Atg7) 62 . Specific inhibition of Atg7 in the lung is sufficient to impair the protective effect of anthracyclines while Atg7 overexpression in the lung is protective against severe sepsis 62 .…”