Lipid-mediated GPR32 signaling reprograms macrophage metabolism to impair anti-tuberculous immunity
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-1α activity and impairing intracellular M. tuberculosis control. HIF-1α stabilization restored antimicrobial function. These findings uncover the RvD5-GPR32-HIF-1α axis as a mechanism of metabolic immune suppression and a potential target for host-directed TB therapy. Abstract Figure
Authors
- Joaquina Barros
- Martín Manuel Ledesma (ORCID: https://orcid.org/0000-0002-9080-2108)
- Ranjan Kumar Nanda (ORCID: https://orcid.org/0000-0002-2163-4411)
- Rafael José Argüello (ORCID: https://orcid.org/0000-0001-9785-3883)
- Florencia Sabbione (ORCID: https://orcid.org/0000-0002-9220-2210)
- Matías Ostrowski (ORCID: https://orcid.org/0000-0002-3982-1338)
- Domingo Palmero (ORCID: https://orcid.org/0000-0002-7496-5492)
- Luciana Balboa (ORCID: https://orcid.org/0000-0001-7045-3572)
- Natacha Faivre (ORCID: https://orcid.org/0009-0008-0330-5519)
- José Luis Marín Franco (ORCID: https://orcid.org/0000-0001-8820-7820)
- Christel Vérollet (ORCID: https://orcid.org/0000-0002-1079-9085)
- Tomás Martín Grosso (ORCID: https://orcid.org/0000-0001-7225-7284)
- Milagro Sánchez Cunto (ORCID: https://orcid.org/0000-0002-8846-2845)
- Sarah Monard (ORCID: https://orcid.org/0000-0001-7149-312X)
- Agustina Juliana Errea (ORCID: https://orcid.org/0009-0005-7796-7804)
- Emilie Layre (ORCID: https://orcid.org/0000-0003-3044-1299)
- Mariano Maio
- Arnaud Métais (ORCID: https://orcid.org/0000-0002-9538-0338)
- Olivier Neyrolles (ORCID: https://orcid.org/0000-0003-0047-5885)
- Federico Fuentes
- Mario José Matteo
- María Emilia Boix
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Academia Nacional de Medicina (AR)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Inserm (FR)
- Aix-Marseille Université (FR)
- Universidad de Buenos Aires (AR)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (AR)
- Hospital Muñiz (AR)
- International Centre for Genetic Engineering and Biotechnology (IN)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Université de Toulouse (FR)
- Universidad Nacional de La Plata (AR)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1007/s00018-026-06480-y
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Fondation Bettencourt Schueller
- MSDAVENIR