Lipid-mediated GPR32 signaling reprograms macrophage metabolism to impair anti-tuberculous immunity

Barros, J.; Maio, M.; Ledesma, M. M.; Boix, M. E.; Faivre, N.; Monard, S.; Franco, J. L. M.; Metais, A.; Sabbione, F.; Fuentes, F.; Grosso, T. M.; Errea, A. J.; Aragone, X.; Cunto, M. S.; Palmero, D.; Matteo, M.; Ostrowski, M.; ARGUELLO, R. J.; Nanda, R.; Layre, E.; Neyrolles, O.; Verolle, C.; Lugo-Villarino, G.; Balboa, L.

doi:10.1101/2025.07.07.663524

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bioRxiv · 10.1101/2025.07.07.663524

Lipid-mediated GPR32 signaling reprograms macrophage metabolism to impair anti-tuberculous immunity

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Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has evolved strategies to evade innate immunity and establish persistent infection. However, the mechanisms by which M. tuberculosis reprograms human macrophage metabolism remain incompletely defined. Tuberculous pleural effusion (TB-PE), a common extrapulmonary manifestation that frequently coexists with pulmonary TB, offers a unique, clinically relevant immunometabolic window into the TB microenvironment. Here, using patient-derived TB-PE samples, we demonstrate that this microenvironment induces a metabolic state in human macrophages that compromises their antimicrobial function. Lipidomic analysis identified an enrichment of the specialized pro-resolving mediator Resolvin D5 (RvD5), which signals through GPR32 to suppress macrophage microbicidal activity. The acellular fraction of TB-PE was sufficient to induce RvD5 secretion by monocytes, correlating with increased expression of RvD5 biosynthetic enzymes in pleural monocytes from TB patients. Mechanistically, RvD5-GPR32 signaling inhibited glycolysis without promoting oxidative phosphorylation, reducing HIF-1 activity and impairing intracellular M. tuberculosis control. HIF-1 stabilization restored antimicrobial function. These findings uncover the RvD5-GPR32-HIF-1 axis as a mechanism of metabolic immune suppression and a potential target for host-directed TB therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/663524v3_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@64feceorg.highwire.dtl.DTLVardef@948ab0org.highwire.dtl.DTLVardef@1d387forg.highwire.dtl.DTLVardef@682f72_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Barros, J., Maio, M., Ledesma, M. M., Boix, M. E., Faivre, N., Monard, S., Franco, J. L. M., Metais, A., Sabbione, F., Fuentes, F., Grosso, T. M., Errea, A. J., Aragone, X., Cunto, M. S., Palmero, D., Matteo, M., Ostrowski, M., ARGUELLO, R. J., Nanda, R., Layre, E., Neyrolles, O., Verolle, C., Lugo-Villarino, G., Balboa, L.. 2025-07-10. Lipid-mediated GPR32 signaling reprograms macrophage metabolism to impair anti-tuberculous immunity. https://doi.org/10.1101/2025.07.07.663524

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