Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Abstract

Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in SLE. However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokines by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

“…All values were Ig deposition was reduced and noticeable improvement in renal damage was observed. In a previous study, we showed no significant differences in autoantibody titers between these strains up to 22 weeks of age 38 ; here, we confirm and further extend this observation up until 38 weeks of age. Both anti-double-stranded DNA and antichromatin antibodies are closely associated with nephritogenicity.…”

“…2,40 Antibodies against ribosomal P (P0, P1, and P2) were measured using a commercially available kit from Aesku Diagnostics (Wendelsheim, Germany). 38 Sera were diluted to 1:100, and OD values were normalized to the average absorbance of sera from two sick control MRL/lpr mice.…”

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

“…This observation also confirms, in the MRL-lpr model, the robustness of emotional dysfunction by providing further evidence that such behavioral outcomes are likely a primary manifestation of autoimmunity rather than arising from nonspecific illness or peripheral organ pathology. Finally, MRLlpr mice also display anhedonia, another manifestation of murine depressive-like behavior [91], which is is a lack of response to pleasure or reward and is assessed experimentally in following the loss of the typical preference to drink sweetened fluids [92]. Anhedonia is classically considered as a hallmark diagnostic symptom of depression and, in this report, it correlates significantly with a depression-like phenotype in the forced-swim test.…”

Temporal Regulation of Glomerular and Cortical Tubulointerstitial Genes Involved in the Development of Nephrotoxic Serum Nephritis

“…Gene expression was analysed using Taqman assays (Life Technologies): Ccl2 (Mm00441242_m1) and Nphs1 (Mm01176615_g1). The values were normalised to GAPDH and RPL27 [8].…”