Targeting the GPR183/EBI2‒oxysterol axis in tuberculosis: Immunometabolic regulation and prospects for host-directed therapy.

BACKGROUND: Tuberculosis (TB), caused predominantly by Mycobacterium tuberculosis (Mtb), remains a major global health challenge despite the availability of antimicrobial chemotherapy. Drug-resistant TB, latent infection, immunopathology and metabolic comorbidities such as diabetes continue to undermine treatment efficacy, highlighting the urgent need for host-directed therapeutic (HDT) strategies that complement antibacterial regimens. G protein-coupled receptors (GPCRs) are highly tractable drug targets that integrate immune and metabolic signals. Among them, GPR183, also known as Epstein‒Barr virus-induced gene 2 (EBI2), has emerged as an oxysterol-sensing receptor with growing relevance to TB pathogenesis. MAIN BODY: GPR183 is activated by oxysterol gradients, particularly 7α,25-dihydroxycholesterol (7α,25-OHC), which is generated via the CH25H‒CYP7B1‒HSD3B7 metabolic axis. This pathway regulates diverse immune functions, including immune-cell positioning, macrophage recruitment, dendritic-cell and lymphocyte localisation, type I interferon restraint and autophagy induction. In the context of TB, reduced GPR183 expression and impaired oxysterol signalling have been linked to disease severity, diabetes-associated susceptibility and defective macrophage antimicrobial responses. CONCLUSION: Collectively, these observations position the GPR183‒oxysterol axis as a potential immunometabolic checkpoint that coordinates macrophage trafficking with autophagic control of intracellular Mtb while simultaneously curbing excessive type I interferon-driven immunopathology. In this review, we summarise current evidence linking GPR183 biology with TB immunity, discuss available pharmacological modulators and GPCR-targeted drug-development challenges, and propose experimental frameworks to evaluate GPR183 as a candidate HDT target for TB.