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

Nadine Radomski1, Danny Kägebein2, Elisabeth Liebler-Tenorio3

  • 1Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Südufer 10, D-17493, Greifswald, Isle of Riems, Germany.

Scientific Reports
|June 22, 2017
PubMed

Insights

Tumor necrosis factor-alpha (TNF-α) triggers a novel pathway where dendritic cells (DCs) use mito-xenophagy to eliminate Chlamydia. This process involves arachidonic acid production, mitochondrial dysfunction, and HDAC6 to enhance bacterial antigen presentation.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Chlamydiae are intracellular bacterial pathogens residing in vacuolar inclusions within host cells.
  • Dendritic cells (DCs) eliminate Chlamydia via auto/xenophagy, a process crucial for antigen presentation.
  • The precise mechanisms governing DC-mediated Chlamydia clearance and immune response activation require further elucidation.

Purpose of the Study:

  • To investigate the role of TNF-α in DC-mediated Chlamydia elimination and antigen presentation.
  • To elucidate the molecular mechanisms, including metabolic and organelle involvement, in this host-pathogen interaction.
  • To identify key regulators and pathways involved in the degradation of Chlamydial inclusions.

Main Methods:

  • Utilized dendritic cells (DCs) infected with Chlamydia.
  • Investigated the role of TNF-α, cytosolic phospholipase A2 (cPLA2), arachidonic acid (AA), and HDAC6.
  • Analyzed mitochondrial function, cellular metabolism (aerobic glycolysis), and autophagy markers (e.g., mito-xenophagy, ubiquitin/autophagy machinery).
  • Assessed chlamydial antigen presentation via MHC I.

Main Results:

  • TNF-α drives cPLA2-mediated AA production, impairing Chlamydia inclusion integrity by disrupting mitochondrial function.
  • DCs undergo a metabolic switch to aerobic glycolysis, promoting cell survival.
  • HDAC6 associates with disintegrated inclusions, further destabilizing them.
  • Bacterial remnants are degraded via mito-xenophagy, involving defective mitochondria, HSP25/27, Parkin, and HDAC6.
  • This pathway enhances chlamydial antigen generation for MHC I presentation.

Conclusions:

  • A novel TNF-α-dependent mito-xenophagic pathway is identified for DC-mediated anti-Chlamydial resistance.
  • This pathway links innate immunity (DC clearance) with adaptive immunity (antigen presentation).
  • The findings highlight the critical role of metabolic reprogramming and organelle dynamics in host defense against bacterial pathogens.

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