Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition.
Jessica GräbIsabelle SuárezEdeltraud van GumpelSandra WinterFynn SchreiberAnna EsserChristoph HölscherMelanie FritschMarc HerbMichael SchrammLaurens WachsmuthChristian PallaschManolis PasparakisHamid KashkarJan RybnikerPublished in: Nature communications (2019)
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).
Keyphrases
- mycobacterium tuberculosis
- cell death
- cell cycle arrest
- pulmonary tuberculosis
- induced apoptosis
- oxidative stress
- end stage renal disease
- rheumatoid arthritis
- pi k akt
- chronic kidney disease
- newly diagnosed
- protein kinase
- ejection fraction
- prognostic factors
- emergency department
- low dose
- high dose
- endothelial cells
- diabetic rats
- signaling pathway
- drug induced
- hepatitis c virus
- cell proliferation
- hiv aids
- adverse drug
- patient reported outcomes
- patient reported
- hiv infected
- antiretroviral therapy