The Endogenous Retinoic Acid Receptor Pathway Is Exploited by Mycobacterium tuberculosis during Infection, Both In Vitro and In Vivo.

Autor:	Tenório de Menezes YK; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Eto C; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., de Oliveira J; Department of Biochemistry and Immunology, Graduate Program in Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Larson EC; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA., Mendes DAGB; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Dias GBM; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Delgobo M; Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany., Gubernat AK; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA., Gleim JL; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA., Munari EL; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Starick M; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Ferreira F; Laboratory of Molecular Genetics of Bacteria, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Mansur DS; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil., Costa DL; Department of Biochemistry and Immunology, Graduate Program in Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Scanga CA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA., Báfica A; Laboratory of Immunobiology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2023 Aug 15; Vol. 211 (4), pp. 601-611.
DOI:	10.4049/jimmunol.2200555
Abstrakt:	Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies. (Copyright © 2023 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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