Scientific Reports (Jun 2017)

Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells

  • Nadine Radomski,
  • Danny Kägebein,
  • Elisabeth Liebler-Tenorio,
  • Axel Karger,
  • Elke Rufer,
  • Birke Andrea Tews,
  • Stefanie Nagel,
  • Rebekka Einenkel,
  • Anne Müller,
  • Annica Rebbig,
  • Michael R. Knittler

DOI
https://doi.org/10.1038/s41598-017-04142-5
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 18

Abstract

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Abstract Chlamydiae are bacterial pathogens that grow in vacuolar inclusions. Dendritic cells (DCs) disintegrate these compartments, thereby eliminating the microbes, through auto/xenophagy, which also promotes chlamydial antigen presentation via MHC I. Here, we show that TNF-α controls this pathway by driving cytosolic phospholipase (cPLA)2-mediated arachidonic acid (AA) production. AA then impairs mitochondrial function, which disturbs the development and integrity of these energy-dependent parasitic inclusions, while a simultaneous metabolic switch towards aerobic glycolysis promotes DC survival. Tubulin deacetylase/autophagy regulator HDAC6 associates with disintegrated inclusions, thereby further disrupting their subcellular localisation and stability. Bacterial remnants are decorated with defective mitochondria, mito-aggresomal structures, and components of the ubiquitin/autophagy machinery before they are degraded via mito-xenophagy. The mechanism depends on cytoprotective HSP25/27, the E3 ubiquitin ligase Parkin and HDAC6 and promotes chlamydial antigen generation for presentation on MHC I. We propose that this novel mito-xenophagic pathway linking innate and adaptive immunity is critical for effective DC-mediated anti-bacterial resistance.