IFNγ-associated immune--metabolic remodeling drives serotonin-kynurenine imbalance with cortical vulnerability in lupus-prone mice

IntroductionNeuropsychiatric systemic lupus erythematosus (NPSLE) is a major clinical challenge, characterized by heterogeneous manifestations and the absence of reliable biomarkers. The mechanisms linking systemic autoimmunity to neuronal injury and neuropsychiatric symptoms remain poorly understood. MethodsUsing the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mapping, cortical metabolomics, and behavioral analyses to dissect immune-metabolic-neuronal interactions. ResultsInflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as the central driver. Composite cytokine scores correlated strongly with plasma NfL, establishing an immune-neuronal injury axis. Region-resolved analyses revealed distinct CNS cytokine signatures, including selective hippocampal loss of interleukin-10 and IFN{gamma}-dominated responses in the frontal cortex. Cortical metabolomics demonstrated diversion of tryptophan metabolism away from serotonin toward the kynurenine pathway, with increased quinolinic acid/kynurenic acid (QA/KA) ratio and upregulation of indoleamine 2,3-dioxygenase-1 (Ido1) and kynurenine 3-monooxygenase (Kmo). NfL levels were negatively associated with serotonin and positively with 3-hydroxykynurenine and QA/KA, linking axonal damage to an excitotoxic metabolic environment. Importantly, cortical serotonin levels correlated with exploratory behavior, linking serotonergic depletion to anxiety-like phenotypes. DiscussionTogether, these results delineate a cascade in which systemic IFN{gamma} is associated with cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood or CSF monitoring of IFN{gamma}, NfL, and kynurenine metabolites could represent a candidate biomarker framework for NPSLE. However, validation in independent patient cohorts will be essential, and therapeutic modulation of IDO1/KMO or serotonergic pathways remains an avenue for future investigation.