Anthracyclines induce DNA damage response-mediated protection against severe sepsis

Nuno Figueiredo, Angelo Chora, Helena Raquel, Nadja Pejanovic, Pedro Pereira, Björn Hartleben, Ana Neves-Costa, Catarina Moita, Dora Pedroso, Andreia Pinto, Sofia Marques, Hafeez Faridi, Paulo Costa, Raffaella Gozzelino, Jimmy L. Zhao, Miguel P. Soares, Margarida Gama-Carvalho, Jennifer Martinez, Qingshuo Zhang, Gerd DöringMarkus Grompe, J. Pedro Simas, Tobias B. Huber, David Baltimore, Vineet Gupta, Douglas R. Green, João A. Ferreira, Luis F. Moita

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates andlimited 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.

Original languageEnglish (US)
Pages (from-to)874-884
Number of pages11
JournalImmunity
Volume39
Issue number5
DOIs
StatePublished - Nov 14 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Figueiredo, N., Chora, A., Raquel, H., Pejanovic, N., Pereira, P., Hartleben, B., Neves-Costa, A., Moita, C., Pedroso, D., Pinto, A., Marques, S., Faridi, H., Costa, P., Gozzelino, R., Zhao, J. L., Soares, M. P., Gama-Carvalho, M., Martinez, J., Zhang, Q., ... Moita, L. F. (2013). Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity, 39(5), 874-884. https://doi.org/10.1016/j.immuni.2013.08.039