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

2016; Nature Portfolio; Volume: 17; Issue: 9 Linguagem: Inglês

10.1038/ni.3509

1529-2916

Johan Garaude, Rebeca Acín‐Pérez, Sarai Martínez-Cano, Michel Enamorado, Matteo Ugolini, Estanislao Nistal‐Villán, Sandra Hervás‐Stubbs, Pablo Pelegrı́n, Leif Erik Sander, José Antonio Enrı́quez, David Sancho,

Sphingolipid Metabolism and Signaling

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.