The TNF-family member cytokine TWEAK has pleotropic effects, including enhancement of the inflammatory milieu and context dependent effects on cell survival and apoptosis. The only confirmed TWEAK receptor, Fn14, is expressed in astrocytes, microglia, endothelial cells, and neurons. Furthermore, TWEAK promotes the release of inflammatory cytokines known to play a role in neuropsychiatric SLE (NPSLE). Recently, we found that Fn14 deficient MRL-lpr/lpr lupus prone mice displayed significantly attenuated depressive-like behavior and improved cognition, while human NPSLE is associated with high TWEAK levels in the CSF. In this proposal we will determine the role of TWEAK Fn14 signaling in NPSLE and its utility as a biomarker and novel therapeutic target by studying TWEAK and Fn14 expression over time in lupus prone mice, assessing the potential of TWEAK to replicate NPSLE-like deficits, and determining the efficacy of anti-TWEAK antibodies in treating neurobehavioral abnormalities in MRL-lpr/lpr mice. Furthermore, we will characterize the effects of TWEAK on the blood brain barrier (BBB) by assessing the effect of TWEAK on BBB permeability in brain microvascular endothelial cells in vitro, measuring the effect of TWEAK on the functional and anatomical integrity of the BBB in vivo, and elucidating the mechanism of TWEAK effects on the BBB.