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

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Tenorio de Menezes, Yonne Karoline ; Eto, Carolina ; de Oliveira, Joseana ; Larson, Erica C. ; Mendes, Daniel A. G. B. ; Malaquias Dias, Greicy Brisa ; Delgobo, Murilo ; Gubernat, Abigail K. ; Gleim, Janelle L. ; Munari, Eduarda Lais ; Starick, Marick ; Ferreira, Fabienne ; Mansur, Daniel Santos ; Costa, Diego L. ; Scanga, Charles A. ; Bafica, Andre

• Document type: Journal article
• Source: JOURNAL OF IMMUNOLOGY; v. 211, n. 4, p. 11-pg., 2023-08-15.

Abstract

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)-6Hnaphthalen-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 23 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. (AU)

• FAPESP's process: 21/13946-6 - Characterization of the role of HIF2a in myeloid leukocytes during infection with Mycobacterium tuberculosis
• Grantee: Joseana de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/08445-8 - Immunomodulation of iron homeostasis and regulation of tyrosine kinase TAM receptor signaling pathway during Mycobacterium tuberculosis infection: targets for the development of host-directed immunopharmacological therapies
• Grantee: Diego Luís Costa
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/25770-0 - Immunomodulation of iron homeostasis and regulation of tyrosine kinase TAM receptor signaling pathway during Mycobacterium tuberculosis infection: targets for the development of host-directed immunopharmacological therapies
• Grantee: Diego Luís Costa
• Support Opportunities: Scholarships in Brazil - Young Researchers