The kynurenine pathway: an immunometabolic bridge linking systemic inflammation to neuroaxonal vulnerability in multiple sclerosis.

Multiple sclerosis (MS) extends beyond focal autoimmune demyelination, with progressive neurodegeneration and cognitive impairment arising from mechanisms not fully explained by inflammatory lesions alone. We propose the kynurenine pathway (KP) as a unifying immunometabolic interface that translates peripheral inflammation into central neuroaxonal vulnerability. Cytokine-driven induction of indoleamine 2,3-dioxygenase accelerates systemic tryptophan catabolism, increasing circulating kynurenine that crosses the blood-brain barrier via L-type amino acid transporter 1 (LAT1). Within the CNS, microglial kynurenine 3-monooxygenase generates the excitotoxic and pro-oxidant metabolites quinolinic acid and 3-hydroxykynurenine, while astrocytic kynurenine aminotransferases produce the neuroprotective antagonist kynurenic acid. This enzymatic dichotomy creates a dynamic amplification loop that intensifies excitotoxicity, oxidative stress, oligodendrocyte injury, and axonal loss. Clinical evidence shows that kynurenine metabolite ratios correlate with plasma neurofilament light chain, cognitive deficits, obesity-related inflammation, and phenotype-specific exercise responsiveness, underscoring KP plasticity as a potential determinant of disease trajectory. By reframing MS through this immunometabolic lens, the KP emerges as both a mechanistic bridge between inflammation and neurodegeneration and a tractable biomarker system with therapeutic potential.