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

Nat Commun. 2019 Feb 8;10(1):688. doi: 10.1038/s41467-019-08405-9.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Dexamethasone / pharmacology
  • Humans
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / metabolism*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / metabolism*
  • Phosphorylation / drug effects
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Adrenal Cortex Hormones
  • Receptors, Tumor Necrosis Factor, Type I
  • Dexamethasone
  • p38 Mitogen-Activated Protein Kinases