Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by involvement of multiple organs, including the central nervous system. While neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) is relatively common and appears early, the underlying mechanisms are not fully understood. TWEAK is a cytokine member of the TNF superfamily; the TWEAK receptor, Fn14, is expressed in brain endothelial cells, astrocytes, microglia and neurons. TWEAK/Fn14 interactions can lead to cytokine production, neuron degeneration, and an increase in blood brain barrier (BBB) permeability. The disruption of the BBB is believed to be a key pathological feature in NPSLE, allowing the passage of neurotoxic autoantibodies into the brain. 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. Similarly, NPSLE patients demonstrate high levels of TWEAK in the cerebrospinal fluid. We undertook the current studies to further investigate the mechanisms by which TWEAK signaling is involved in the pathogenesis of NPSLE.
Comprehensive neurobehavioral assessment including forced swim, anhedonia, open field, object recognition, object placement, and social preference were employed to quantify neuropsychiatric manifestations in MRL/lpr Fn14WT and MRL/lpr Fn14KO mice at 20 weeks of age. Mice were sacrificed after behavior profiling, and the brains prepared for qRT-PCR, Western blot and immunohistochemistry (IHC). To assess blood brain barrier (BBB) integrity, Western blot was performed to evaluate extravascular fibronectin and IgG deposition (which both increase with BBB permeability). Additionally, cellular infiltrates were quantified on hematoyxlin and eosin staining. Fluoro Jade B and TUNEL staining were used 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.
We found that Fn14KO mice had improved BBB integrity, as shown by decreased fibronectin and IgG deposition in the brain. However, no clear differences in the magnitude of cellular infiltrates were observed in the choroid plexus. Additionally, neuronal damage, another important pathological change that can be seen in experimental NPSLE, 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. Studies to compare cytokine expression in brain and cerebrospinal fluid of Fn14KO and Fn14WT mice are in progress.
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 challenging disease manifestation.
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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/