IFNγ-associated immune–metabolic remodeling is linked to serotonin–kynurenine imbalance and cortical vulnerability in lupus-prone mice

Introduction Neuropsychiatric 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. Methods Using the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mRNA mapping, cortical metabolomics, and behavioral analyses to dissect immune–metabolic–neuronal interactions. Results Inflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as a prominent component of the inflammatory profile. 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 IFNγ-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. Discussion Together, these results support an associative framework in which systemic IFNγ levels are linked to cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood-based monitoring of IFNγ, NfL, and kynurenine metabolites may 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.