A tau-NLRP3 neuroimmune loop in the lateral septum drives chronic pain and anxiety comorbidity

The excitability imbalance in the lateral septum (LS) has been recognized as a critical neural basis for chronic pain-anxiety comorbidity. However, the downstream molecular mechanisms triggered by this imbalance, as well as the bidirectional crosstalk between neurons and glia within the LS, remain poorly understood. Employing a complete Freund’s adjuvant model, we identified enhanced excitability of LS GABAergic neurons as a direct driver of chronic inflammatory pain and comorbid anxiety. Neuronal activation directly increases tau expression in the LS. Neuronal tau overexpression or tau ablation exacerbated or alleviated pain hypersensitivity and anxiety-like behaviors, respectively. The anterior cingulate cortex tau manipulation exhibited no effect, confirming the specificity of LS. Mechanistic studies have revealed that hyperactive neurons release tau proteins, which was internalized by microglia through CX3CR1 receptors. Internalized tau induced NF-κB phosphorylation and upregulated NLRP3 inflammasomes, resulting in the secretion of IL-1β. Extracellular IL-1β then bound to neuronal IL-1R1, enhancing neuronal excitability and forming a positive feedback loop, where neuronal activation drove tau release, microglial inflammation, and reciprocal neuronal sensitization. Systemic clonidine administration disrupted this neuroimmune axis and concurrently alleviated pain and anxiety. These findings reveal a novel neuroimmune circuit mechanism that bridges neuronal hyperactivity and glial inflammation in pain-affective comorbidities, providing a therapeutic framework for dual-target intervention strategies.