The pathogenesis of neuropsychiatric lupus
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Neuropsychiatrie disease (NPSLE) is one of the most common manifestations of human systemic lupus erythematosus (SLE), but the mechanisms remain poorly understood. Two leading hypotheses in understanding the pathogenesis of NPSLE are believed to be cytokine-induced brain inflammation and/or B cell (autoantibody) mediated central nervous system (CNS) compromise.;TWEAK is a cytokine belonging to the TNF family; its sole signaling receptor is Fn14. TWEAK/Fn14 interactions mediate pleotropic effects, including cell proliferation, cell death and inflammation. Clinical studies demonstrate that TWEAK is upregulated in the cerebrospinal fluid (CSF) of NPSLE patients and maybe a potential biomarker for NPSLE. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of NPSLE. To test this hypothesis, a comprehensive battery of neurobehavioral tests was conducted to evaluate neuropsychiatrie disease in age- and gender-matched lupus prone MRL/lpr Fn14 wild type (WT) and knockout (KO) mice. We found that MRL/lpr Fn14WT mice displayed profound depressive-like behavior and impaired cognitive function, which were significantly ameliorated in Fn14KO mice. To further investigate the mechanisms of TWEAK signaling in the pathogenesis of NPSLE, we assessed brain histopathology and inflammatory mediator expression in Fn14WT and Fn14KO mice. We found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus, preserved blood brain barrier (BBB) permeability, attenuated inflammatory mediators including CCL5, C3 and iNOS, as well as reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Additionally, we found that MRL/lpr Fnl4KO mice manifested reduced neuron degeneration and hippocampal gliosis. However, there were no significant differences in the serum autoantibody titers between MRL/lpr Fnl4WT and KO mice.;To further investigate whether this improvement in disease is due to the inhibition of TWEAK/Fn14 signaling within the CNS rather than in the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular injection (ICV) of Fe-TWEAK or an isotype matched control protein to non-autoimmune C57B16/J mice. Interestingly, Fc-TWEAK injected animals displayed similar neuropsychiatric manifestations and histological findings to MRL/lpr mice. Thus, our study indicates that TWEAK/Fn14 signaling within the CNS play an important role in the pathogenesis NPSLE by disrupting BBB integrity, enhancing neuroinflammation, and increasing neuronal damage, suggesting a novel target for CNS inflammatory diseases.;Apart from cytokine-induced brain inflammation, B cells/autoantibodies are also believed to play an important role in the pathogenesis of NPSLE. In lupus, a compromised blood brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can induce neuropsychiatric abnormalities including depressive-like behavior and cognitive dysfunction. To support a possible role of B cells in the pathogenesis of NPSLE, we evaluated neuropsychiatric disease in constitutively B- cell deficient (JhD/MRL/lpr) and conditionally B-cell depleted mice (hCD20DTA/MRL/lpr, inducible by tamoxifen), as compared to MRL/lpr lupus mice. We found that autoantibody levels were negligible (JhD/MRL/lpr) or significantly reduced (hCD20DTA/MRL/lpr) in the serum and CSF, respectively. Nevertheless, both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice showed profound depressive-like behavior, which was not significantly different from MRL/lpr mice. Cognitive deficits were also observed in both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice, similar to the MRL/lpr mice. Furthermore, B cell deficient and depleted mice exhibited increased blood brain barrier permeability, elevated brain cell apoptosis and upregulated cytokine production. Therefore, for the first time, our study indicates that B cells/autoantibodies are not required for the pathogenesis of murine NPSLE, at least in MRL/lpr strain.
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