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

Jessica Gräb, Isabelle Suárez, Edeltraud Gumpel, Sandra Winter, Fynn Schreiber, Anna Esser, Christoph Hölscher, Melanie Fritsch, Marc Herb, Michael Schramm, Laurens Wachsmuth, Christian Pallasch, Manolis Pasparakis, Hamid Kashkar and Jan Rybniker ()
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Jessica Gräb: University of Cologne
Isabelle Suárez: University of Cologne
Edeltraud Gumpel: University of Cologne
Sandra Winter: University of Cologne
Fynn Schreiber: University of Cologne
Anna Esser: University of Cologne
Christoph Hölscher: German Center for Infection Research (DZIF), Partner Site Bonn-Cologne
Melanie Fritsch: University of Cologne
Marc Herb: University of Cologne
Michael Schramm: University of Cologne
Laurens Wachsmuth: University of Cologne
Christian Pallasch: University of Cologne
Manolis Pasparakis: University of Cologne
Hamid Kashkar: University of Cologne
Jan Rybniker: University of Cologne

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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).

Date: 2019
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DOI: 10.1038/s41467-019-08405-9

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