Background/Purpose: While neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) is relatively common and appears early, the underlying mechanisms are not fully understood. The disruption of the blood brain barrier (BBB) is believed to be one key pathological feature in NPSLE, allowing the passage of neurotoxic autoantibodies into the brain.

   TWEAK is a cytokine member of the TNF superfamily; the TWEAK receptor, Fn14, is expressed in brain endothelial cells, astrocytes, microglia and neurons. We recently found that lupus prone MRL/lpr Fn14 knockout (KO) mice display a markedly attenuated neuropsychiatric phenotype, as revealed by a significant reduction in depressive-like behavior and improved cognitive function. Morever, NPSLE patients demonstrate high levels of TWEAK in the cerebrospinal fluid (CSF). We undertook the current studies to determine the mechanisms by which TWEAK signaling is involved in the pathogenesis of NPSLE.

Methods: Brains from female MRL/lpr Fn14WT and MRL/lpr Fn14KO mice at 20 weeks of age were prepared for qRT-PCR, Western blot and immunohistochemistry (IHC). Cellular infiltrates were quantified by hematoyxlin and eosin staining. To assess BBB integrity, extravascular fibronectin and IgG deposition, VCAM/ICAM, and iNOS expression was evaluated by Western blot, IHC and qPRT-PCR, respectively. Complement activation was assessed by measuring the expression of C3, C4a and C6 by qRT-PCR and Western blot. Fluoro Jade B and TUNEL staining were employed to analyze neuronal damage and apoptosis in the brain. Furthermore, gliosis, neuron loss, and neurogenesis were assessed by immunostaining with GFAP, NeuN and Ki-67, respectively.

Results: We found that MRL/lpr Fn14KO mice had significantly improved BBB integrity, as shown by a lower CSF albumin index, decreased fibronectin and IgG deposition, and reduced brain expression of VCAM, ICAM and iNOS. Furthermore, Fn14KO mice exhibited significantly fewer cellular infiltrates in the choroid plexus compared to the Fn14WT mice. At the same time, a significant reduction in C3, C4a and C6 expression was observed in brains of Fn14KO mice. Neuronal damage, an important pathological change present in lupus animal models, was also ameliorated by Fn14 deficiency. Fn14KO mice displayed reduced apoptosis in the cortex, as well as less neuron loss and less gliosis in the hippocampus. Interestingly, there were no differences in neurogenesis and in microglia activation between Fn14KO and Fn14WT mice.

Conclusion: Our studies indicate that TWEAK/Fn14 interactions can play a central role in the pathogenesis of NPSLE by improving BBB integrity and reducing neuronal damage, suggesting this pathway as a novel target for therapeutic intervention in this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibiting-tweak-tnf-like-weak-inducer-of-apoptosis-signaling-improves-blood-brain-barrier-integrity-and-protects-from-neuronal-damage-in-murine-neuropsychiatric-lupus-2/