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 TPE 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. Significance statement Tuberculosis (TB) persists as a global threat because Mycobacterium tuberculosis hijacks host lipid metabolism to subvert immunity. This study investigates how TB-induced host lipids reprogram macrophage metabolism to weaken their antimicrobial activity. We show that tuberculous pleural effusion, a fluid accumulation in the pleural cavity, is enriched with the lipid mediator Resolvin D5 (RvD5). RvD5 impairs macrophage function by blocking glycolysis via the GPR32 receptor, leading to an energy-deficient state that compromises bacteria killing. Remarkably, restoring the metabolic regulator HIF-1α rescues this antimicrobial defect. By revealing a mechanism through which TB exploits host-derived lipids to evade immune control, this work deepens our understanding of infection-induced immune dysfunction and highlights potential therapeutic targets for TB and other infectious diseases.