Metabolite-Driven Immunometabolic Crosstalk in Intervertebral Disc Degeneration: The Macrophage-Disc Cell Interface.
- 1Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.
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.
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BibTeX
@article{ma2026metabolitedriven,
title = {{Metabolite-Driven Immunometabolic Crosstalk in Intervertebral Disc Degeneration: The Macrophage-Disc Cell Interface.}},
author = {Dong Ma and Jirong Zhao and Kaijie Guo and Wulong Liu and Hongnian Yin and Yang Zhan and Rui Zhao and Jing Wang and Tong Ma},
journal = {Journal of inflammation research},
year = {2026},
month = nov,
doi = {10.2147/jir.s651180},
url = {https://europepmc.org/article/MED/42999835},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Metabolite-Driven Immunometabolic Crosstalk in Intervertebral Disc Degeneration: The Macrophage-Disc Cell Interface.
AU - Dong Ma
AU - Jirong Zhao
AU - Kaijie Guo
AU - Wulong Liu
AU - Hongnian Yin
AU - Yang Zhan
AU - Rui Zhao
AU - Jing Wang
AU - Tong Ma
PY - 2026
DA - 2026/11/03
JO - Journal of inflammation research
DO - 10.2147/jir.s651180
UR - https://europepmc.org/article/MED/42999835
AB - 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.
SN - 1178-7031
ER -