Graeb, Jessica, Suarez, Isabelle, van Gumpel, Edeltraud, Winter, Sandra, Schreiber, Fynn, Esser, Anna, Hoelscher, Christoph, Fritsch, Melanie, Herb, Marc ORCID: 0000-0002-7533-0288, Schramm, Michael, Wachsmuth, Laurens, Pallasch, Christian, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Kashkar, Hamid and Rybniker, Jan (2019). Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 TNF alpha-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).

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Graeb, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suarez, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Gumpel, EdeltraudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreiber, FynnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esser, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritsch, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herb, MarcUNSPECIFIEDorcid.org/0000-0002-7533-0288UNSPECIFIED
Schramm, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachsmuth, LaurensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rybniker, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-156817
DOI: 10.1038/s41467-019-08405-9
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MAP KINASE; P38 MAPK; APOPTOSIS; P53; PROTEIN; SUSCEPTIBILITY; HEXOKINASE; BACTERIAL; DEXAMETHASONE; MACROPHAGESMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15681

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