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

• Published in: Nature communications Vol. 10; no. 1; pp. 688 - 14
• Main Authors: Gräb, Jessica, Suárez, Isabelle, van Gumpel, Edeltraud, Winter, Sandra, Schreiber, Fynn, Esser, Anna, Hölscher, Christoph, Fritsch, Melanie, Herb, Marc, Schramm, Michael, Wachsmuth, Laurens, Pallasch, Christian, Pasparakis, Manolis, Kashkar, Hamid, Rybniker, Jan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/89; 13/95; 14/34; 49/88; 49/98; 631/250/1932; 631/250/2161; 631/250/254; 631/326/41/2533; 64/60; 82/80; Adrenal Cortex Hormones - pharmacology; Apoptosis; Cell death; Corticoids; Corticosteroids; Dephosphorylation; Dexamethasone; Dexamethasone - pharmacology; Humanities and Social Sciences; Humans; Kinases; MAP kinase; MAP kinase phosphatase; Membrane permeability; Mitochondria; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mortality; multidisciplinary; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Necroptosis; p38 Mitogen-Activated Protein Kinases - metabolism; Permeability; Phosphorylation - drug effects; Protein kinase; Proteins; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Signal Transduction - physiology; Tuberculosis; Tumor necrosis factor receptor 1; Tumor necrosis factor receptors; Tumor necrosis factor-α
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08405-9

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). Corticosteroids are host-directed drugs that enhance survival of tuberculosis patients through unclear mechanisms. Here, Gräb et al. show that corticosteroids inhibit necrotic death of cells infected with Mycobacterium tuberculosis by facilitating MKP-1-dependent dephosphorylation of p38 MAPK.