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Nat Immunol. 2016 Sep;17(9):1037-1045. doi: 10.1038/ni.3509. Epub 2016 Jun 27.

Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense.

Author information

1
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
2
Institute for Regenerative Medicine and Biotherapies, Institut National pour la Santé et la Recherche Médicale, U1183, Montpellier, France.
3
Department of Infectious Diseases and Pulmonary Medicine, Charité Hospital Berlin, Berlin, Germany.
4
Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
5
Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
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.
7
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
#
Contributed equally

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.

PMID:
27348412
PMCID:
PMC4994870
DOI:
10.1038/ni.3509
[Indexed for MEDLINE]
Free PMC Article

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