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

Abstract

Abstract 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.