Metabolite-Driven Immunometabolic Crosstalk in Intervertebral Disc Degeneration: The Macrophage-Disc Cell Interface

Abstract: Intervertebral disc degeneration (IVDD) is accompanied by extracellular-matrix disruption, metabolic stress and immune-cell infiltration, but how metabolites mediate communication between disc cells and macrophages remains incompletely defined. This narrative review examines lactate, succinate and kynurenine as candidate signalling metabolites at the macrophage-disc cell interface and proposes an integrative metabolite-centred framework. Evidence is strongest for lactate, which is supported by IVDD-specific studies linking glycolytic adaptation and impaired clearance to acidosis, MCT-dependent metabolic coupling, ASIC/NLRP3 activation, lactylation, cellular senescence and matrix catabolism. Evidence for succinate is more limited: IVDD-specific studies support SIRT5-AIFM1-dependent succinylation and mitochondrial dysfunction, whereas succinate accumulation and SUCNR1-mediated macrophage signalling in human degenerative discs remain unverified. The kynurenine-AhR axis is primarily hypothesis-generating; emerging IVDD-related observations implicate AhR and tryptophan-pathway changes, but a causal kynurenine-AhR macrophage-disc pathway has not been established. We propose that degenerating disc cells may reprogramme the local metabolic microenvironment, thereby altering macrophage functional states and creating a self-amplifying immunometabolic loop that feeds back on disc-cell injury and extracellular-matrix degradation. Future studies should combine spatial immunometabolomics in human tissue with cell-specific and causal intervention experiments to distinguish established mechanisms from context-dependent or extrapolated pathways and to evaluate potential microenvironment-directed therapeutic targets. Keywords: intervertebral disc degeneration, immunometabolism, lactate, succinate, kynurenine, macrophages