Abstract

Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability–specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.

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Acknowledgements

We thank A. Hidalgo for critical reading of the manuscript; S. Akira (Osaka University) for Ips1−/− mice; J. Magarian Blander (Mount Sinai School of Medicine) for Myd88−/−, Trif−/− and Trif−/−Myd88−/− mice; F. Norel-Bozouklian (Institut Pasteur) for S. thyphimurium SL1344; S. Trombetta (New York University) for the plasmid encoding GFP-OT; S. Bartlett for English editing; and M. Fernández-Monreal, M. Villalba, F. Ruperez-Pascualena and members of the Sancho and Enríquez laboratories for discussions and support. Supported by the European Community (FP7-Marie Curie-CIG#332881 to J.G.; ERC-2010-StG 260414 and 635122-PROCROP H2020 to D.S.; and UE0/MCA1108 and UE0/MCA1201 to J.A.E.), the French association 'La Ligue Contre le Cancer-comité du Gard' (CG/59-2013 to J.G.), the Spanish Ministry of Economy and Competitiveness (SAF-2013-42920R to D.S.; SAF2012-1207 to J.A.E.; and RyC2011-07826 to R.A.-P.), the Comunidad de Madrid (CAM/API1009 to J.A.E.), the German research council (DFG grant SA1940/2-1 and SFB-TR84 TP-C08 to L.E.S.). CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

Author information

Author notes

    • Estanislao Nistal-Villán

    Present address: Microbiology Section, Department of Pharmaceutical and Health Science, Faculty of Pharmacy, University CEU San Pablo, Madrid, Spain.

    • Johan Garaude
    •  & Rebeca Acín-Pérez

    These authors contributed equally to this work.

    • Johan Garaude
    • , José A Enríquez
    •  & David Sancho

    These authors jointly supervised this work.

Affiliations

  1. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

    • Johan Garaude
    • , Rebeca Acín-Pérez
    • , Sarai Martínez-Cano
    • , Michel Enamorado
    • , José A Enríquez
    •  & David Sancho
  2. Institute for Regenerative Medicine and Biotherapies, Institut National pour la Santé et la Recherche Médicale, U1183, Montpellier, France.

    • Johan Garaude
  3. Department of Infectious Diseases and Pulmonary Medicine, Charité Hospital Berlin, Berlin, Germany.

    • Matteo Ugolini
    •  & Leif E Sander
  4. Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.

    • Estanislao Nistal-Villán
    •  & Sandra Hervás-Stubbs
  5. Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.

    • Sandra Hervás-Stubbs
  6. Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca (IMIB-Arrixaca), Murcia, Spain.

    • Pablo Pelegrín
  7. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.

    • José A Enríquez

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Contributions

J.G. and R.A.-P. designed and performed all experiments; S.M.-C. and M.E. performed experiments measuring oxidative-phosphorylation enzymatic activity, prepared samples for BN-PAGE and immunoblot analysis and helped with experiments with mice; M.U. and L.E.S. performed experiments with human monocytes; E.N.-V. and S.H.-S. provided bone marrow progenitor cells from STING-deficient and MAVS-deficient mice and generated MAVS-deficient Trif−/− mice; P.P. provided Nlrp3−/− and Casp1−/−Casp11−/− mice; and J.G., R.A.-P., J.A.E. and D.S. directed the study, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Johan Garaude or José A Enríquez or David Sancho.

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https://doi.org/10.1038/ni.3509

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