Universität zu Köln

Steiger, Julia, Stephan, Alexander, Inkeles, Megan S., Realegeno, Susan, Bruns, Heiko, Kroell, Philipp, Kroner, Juliana de Castro, Sommer, Andrea, Batinica, Marina, Pitzler, Lena, Kalscheuer, Rainer ORCID: 0000-0002-3378-2067, Hartmann, Pia, Plum, Georg, Stenger, Steffen, Pellegrini, Matteo ORCID: 0000-0001-9355-9564, Brachvogel, Bent, Modlin, Robert L. and Fabri, Mario (2016). Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity against Mycobacterium bovis Bacille Calmette-Guerin in Glucocorticoid-Treated Human Macrophages. J. Immunol., 197 (1). S. 222 - 233. BETHESDA: AMER ASSOC IMMUNOLOGISTS. ISSN 1550-6606

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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-gamma, 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-gamma 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-gamma, failed to trigger expression and phagolyso-some 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Steiger, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Stephan, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Inkeles, Megan S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Realegeno, Susan UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroell, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroner, Juliana de Castro UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommer, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Batinica, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pitzler, Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalscheuer, Rainer UNSPECIFIED orcid.org/0000-0002-3378-2067 UNSPECIFIED Hartmann, Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Plum, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Stenger, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Pellegrini, Matteo UNSPECIFIED orcid.org/0000-0001-9355-9564 UNSPECIFIED Brachvogel, Bent UNSPECIFIED UNSPECIFIED UNSPECIFIED Modlin, Robert L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabri, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271178
DOI:	10.4049/jimmunol.1502407
Journal or Publication Title:	J. Immunol.
Volume:	197
Number:	1
Page Range:	S. 222 - 233
Date:	2016
Publisher:	AMER ASSOC IMMUNOLOGISTS
Place of Publication:	BETHESDA
ISSN:	1550-6606
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NITRIC-OXIDE SYNTHASE; VITAMIN-D-RECEPTOR; ACTIVATION PATHWAYS; GENE-EXPRESSION; CUTTING EDGE; TUBERCULOSIS; CATHELICIDIN; AUTOPHAGY; GAMMA; BCG Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27117