title: Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity against Mycobacterium bovis Bacille Calmette-Guérin in Glucocorticoid-Treated Human Macrophages.
abstract: Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-γ, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-γ stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H(+)-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-γ, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H(+)-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Stephan
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095;
authors.forename: Megan S
authors.initials: MS
authors.lastname: Inkeles
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095;
authors.forename: Susan
authors.identifier: 0000-0002-1772-510X
authors.initials: S
authors.lastname: Realegeno
authors.affiliation: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, Erlangen 91054, Germany;
authors.forename: Heiko
authors.initials: H
authors.lastname: Bruns
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany;
authors.forename: Philipp
authors.initials: P
authors.lastname: Kröll
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany; Center for Molecular Medicine, University of Cologne, Cologne 50937, Germany;
authors.forename: Juliana
authors.initials: J
authors.lastname: de Castro Kroner
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany; Center for Molecular Medicine, University of Cologne, Cologne 50937, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany;
authors.forename: Marina
authors.initials: M
authors.lastname: Batinica
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, Cologne 50937, Germany;
authors.forename: Lena
authors.initials: L
authors.lastname: Pitzler
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany;
authors.forename: Rainer
authors.identifier: 0000-0002-3378-2067
authors.initials: R
authors.lastname: Kalscheuer
authors.affiliation: 1st Department of Internal Medicine, University of Cologne, Cologne 50937, Germany; Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne 50935, Germany;
authors.forename: Pia
authors.identifier: 0000-0003-4174-3268
authors.initials: P
authors.lastname: Hartmann
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne 50935, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Plum
authors.affiliation: Institute for Medical Microbiology and Hygiene, University Hospital of Ulm, Ulm 89081, Germany;
authors.forename: Steffen
authors.identifier: 0000-0001-5471-0807
authors.initials: S
authors.lastname: Stenger
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095;
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, Cologne 50937, Germany; Department of Pediatrics and Adolescent Medicine, Medical Faculty, University of Cologne, Cologne 50937, Germany; and.
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095; Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Robert L
authors.identifier: 0000-0003-4720-031X
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50937, Germany; Center for Molecular Medicine, University of Cologne, Cologne 50937, Germany; mario.fabri@uk-koeln.de.
authors.forename: Mario
authors.initials: M
authors.lastname: Fabri
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology*; D001343:Autophagy; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D009163:Mycobacterium bovis / Q000276:immunology*; D010588:Phagosomes / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents; D005938:Glucocorticoids; C472421:TCIRG1 protein, human; D007371:Interferon-gamma; D000068877:Imatinib Mesylate; D025262:Vacuolar Proton-Translocating ATPases; D054804:Cathelicidins