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Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition

Author

Listed:
  • Jessica Gräb

    (University of Cologne
    University of Cologne)

  • Isabelle Suárez

    (University of Cologne
    German Center for Infection Research (DZIF), Partner Site Bonn-Cologne)

  • Edeltraud Gumpel

    (University of Cologne
    University of Cologne)

  • Sandra Winter

    (University of Cologne
    University of Cologne)

  • Fynn Schreiber

    (University of Cologne
    University of Cologne)

  • Anna Esser

    (University of Cologne
    University of Cologne)

  • Christoph Hölscher

    (German Center for Infection Research (DZIF), Partner Site Bonn-Cologne
    German Center for Infection Research (DZIF))

  • Melanie Fritsch

    (University of Cologne
    University of Cologne
    University of Cologne)

  • Marc Herb

    (University of Cologne
    University of Cologne)

  • Michael Schramm

    (University of Cologne
    University of Cologne)

  • Laurens Wachsmuth

    (University of Cologne)

  • Christian Pallasch

    (University of Cologne
    University of Cologne)

  • Manolis Pasparakis

    (University of Cologne
    University of Cologne
    University of Cologne)

  • Hamid Kashkar

    (University of Cologne
    University of Cologne
    University of Cologne)

  • Jan Rybniker

    (University of Cologne
    University of Cologne
    German Center for Infection Research (DZIF), Partner Site Bonn-Cologne)

Abstract

Corticosteroids are host-directed drugs with proven beneficial effect on survival of tuberculosis (TB) patients, but their precise mechanisms of action in this disease remain largely unknown. Here we show that corticosteroids such as dexamethasone inhibit necrotic cell death of cells infected with Mycobacterium tuberculosis (Mtb) by facilitating mitogen-activated protein kinase phosphatase 1 (MKP-1)-dependent dephosphorylation of p38 MAPK. Characterization of infected mixed lineage kinase domain-like (MLKL) and tumor necrosis factor receptor 1 (TNFR1) knockout cells show that the underlying mechanism is independent from TNFα-signaling and necroptosis. Our results link corticosteroid function and p38 MAPK inhibition to abrogation of necrotic cell death mediated by mitochondrial membrane permeability transition, and open new avenues for research on novel host-directed therapies (HDT).

Suggested Citation

  • Jessica Gräb & Isabelle Suárez & Edeltraud Gumpel & Sandra Winter & Fynn Schreiber & Anna Esser & Christoph Hölscher & Melanie Fritsch & Marc Herb & Michael Schramm & Laurens Wachsmuth & Christian Pal, 2019. "Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08405-9
    DOI: 10.1038/s41467-019-08405-9
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