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 Döring; Markus Grompe; J. Pedro Simas; Tobias B. Huber; David Baltimore; Vineet Gupta; Douglas R. Green; João A. Ferreira; Luis F. Moita

doi:10.1016/j.immuni.2013.08.039

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

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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 language	English (US)
Pages (from-to)	874-884
Number of pages	11
Journal	Immunity
Volume	39
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2013.08.039
State	Published - Nov 14 2013

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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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

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, JL, Soares, MP, Gama-Carvalho, M, Martinez, J, Zhang, Q, Döring, G, Grompe, M, Simas, JP, Huber, TB, Baltimore, D, Gupta, V, Green, DR, Ferreira, JA & Moita, LF 2013, 'Anthracyclines induce DNA damage response-mediated protection against severe sepsis', Immunity, vol. 39, no. 5, pp. 874-884. https://doi.org/10.1016/j.immuni.2013.08.039

@article{0e784fd14fdc4a1ca52e74ce255a0d69,

title = "Anthracyclines induce DNA damage response-mediated protection against severe sepsis",

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.",

author = "Nuno Figueiredo and Angelo Chora and Helena Raquel and Nadja Pejanovic and Pedro Pereira and Bj{\"o}rn Hartleben and Ana Neves-Costa and Catarina Moita and Dora Pedroso and Andreia Pinto and Sofia Marques and Hafeez Faridi and Paulo Costa and Raffaella Gozzelino and Zhao, {Jimmy L.} and Soares, {Miguel P.} and Margarida Gama-Carvalho and Jennifer Martinez and Qingshuo Zhang and Gerd D{\"o}ring and Markus Grompe and Simas, {J. Pedro} and Huber, {Tobias B.} and David Baltimore and Vineet Gupta and Green, {Douglas R.} and Ferreira, {Jo{\~a}o A.} and Moita, {Luis F.}",

note = "Funding Information: We are grateful to Vasco Barreto for Atm −/− and Frederick Alt for Atm loxP/loxP mice. We thank Mario Ramirez for bacterial strains to probe epirubicin protection in different models of sepsis. The authors greatly appreciate the critical contribution of Professor Gerd D{\"o}ring, who sadly passed away before the publication of this manuscript. L.F.M. receives support from FLAD and FCT (grants PTDC/SAU-IMU/110303/2009, PTDC/SAU-MII/100780/2008, and PTDC/SAU-IMU/110303/2009), A.C. receives support from FCT (PTDC/SAU-IMU/110303/2009), J.A.F. receives support from a Gulbenkian grant (96526/2009), and P.P. is an FCT fellow (SFRH/BD/45502/2008). ",

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doi = "10.1016/j.immuni.2013.08.039",

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pages = "874--884",

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T1 - Anthracyclines induce DNA damage response-mediated protection against severe sepsis

AU - Figueiredo, Nuno

AU - Chora, Angelo

AU - Raquel, Helena

AU - Pejanovic, Nadja

AU - Pereira, Pedro

AU - Hartleben, Björn

AU - Neves-Costa, Ana

AU - Moita, Catarina

AU - Pedroso, Dora

AU - Pinto, Andreia

AU - Marques, Sofia

AU - Faridi, Hafeez

AU - Costa, Paulo

AU - Gozzelino, Raffaella

AU - Zhao, Jimmy L.

AU - Soares, Miguel P.

AU - Gama-Carvalho, Margarida

AU - Martinez, Jennifer

AU - Zhang, Qingshuo

AU - Döring, Gerd

AU - Grompe, Markus

AU - Simas, J. Pedro

AU - Huber, Tobias B.

AU - Baltimore, David

AU - Gupta, Vineet

AU - Green, Douglas R.

AU - Ferreira, João A.

AU - Moita, Luis F.

N1 - Funding Information: We are grateful to Vasco Barreto for Atm −/− and Frederick Alt for Atm loxP/loxP mice. We thank Mario Ramirez for bacterial strains to probe epirubicin protection in different models of sepsis. The authors greatly appreciate the critical contribution of Professor Gerd Döring, who sadly passed away before the publication of this manuscript. L.F.M. receives support from FLAD and FCT (grants PTDC/SAU-IMU/110303/2009, PTDC/SAU-MII/100780/2008, and PTDC/SAU-IMU/110303/2009), A.C. receives support from FCT (PTDC/SAU-IMU/110303/2009), J.A.F. receives support from a Gulbenkian grant (96526/2009), and P.P. is an FCT fellow (SFRH/BD/45502/2008).

PY - 2013/11/14

Y1 - 2013/11/14

N2 - 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.

AB - 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.

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JF - Immunity

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ER -

Anthracyclines induce DNA damage response-mediated protection against severe sepsis

Abstract

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