Inhibiting TWEAK (TNF-like weak inducer of apoptosis) signaling ameliorates blood brain barrier integrity and neuronal damage in neuropsychiatric lupus prone MRL/lpr mice (CCR3P.212)

Abstract

Abstract Neuropsychiatric disease (NPSLE) is one of the most common manifestations of human lupus, but remains poorly understood. TWEAK is a cytokine member of the TNF superfamily; its sole receptor, Fn14, is expressed in brain endothelial cells, astrocytes, microglia and neurons. In vitro, TWEAK signaling promotes expression of MCP-1, IL-6 and IL-8, decreases ZO-1 expression, and increases the permeability of human brain microvascular endothelial cells. Our previous study showed that Fn14 knockout (KO) in the MRL/lpr lupus strain led to markedly attenuated neuropsychiatric disease, as revealed by significant reduction in depressive-like behavior and improved cognitive function. The purpose of the present study was to determine the mechanisms by which TWEAK signaling is instrumental in the pathogenesis of NPSLE. We found that Fn14KO mice had improved BBB integrity as shown by decreased fibronectin and IgG deposition in the brain. Further, there were fewer cellular infiltrates in Fn14KO mice. Additionally, Fn14KO mice displayed reduced neuron apoptosis and hippocampal gliosis. Interestingly, there were no differences in neurogenesis and microglia activation, or in circulating autoantibody titers, between Fn14KO and Fn14WT mice. Our studies indicate that TWEAK/Fn14 interactions play a central role in the pathogenesis of NPSLE by improving BBB integrity and reducing neuronal damage, suggesting a novel target for therapeutic intervention for this major disease manifestation.