Intracerebroventricular TWEAK (TNF-like weak inducer of apoptosis) induces depressive-like behavior and cognitive dysfunction in non-autoimmune mice (CCR5P.200)

Abstract Fn14, the sole receptor for the TNF family member TWEAK, is inducibly expressed in the brain in endothelial cells, astrocytes, microglia, and neurons. Previously, we had found that Fn14 knockout lupus MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To establish whether this improvement in disease is secondary to ablation of TWEAK-Fn14 signaling within the CNS or the periphery and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebraventricular injection (ICV) of Fc-TWEAK or a control protein to B6 mice. Interestingly, we found that the Fc-TWEAK injected mice developed significant depressive-like behavior and abnormal cognitive dysfunction. Inflammatory mediators including MCP-1, C3, and iNOS were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased BBB disruption, as demonstrated by increased fibronectin deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex, hippocampus, and brain stem. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits by acting within the CNS to enhance production of inflammatory mediators, promote permeability of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.