TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice

Abstract

Neuropsychiatric disease is one of the most common manifestations of human systemic lupus erythematosus, but the mechanisms remain poorly understood. In human brain microvascular endothelial cells in vitro, TNF-like weak inducer of apoptosis (TWEAK) decreases tight junction ZO-1 expression and increases the permeability of monolayer cell cultures. Furthermore, knockout (KO) of the TWEAK receptor, Fn14, in the MRL/lpr lupus mouse strain markedly attenuates neuropsychiatric disease, as demonstrated by significant reductions 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 neuropsychiatric lupus (NPSLE). Evaluating brain sections of MRL/lpr Fn14WT and Fn14KO mice, we found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus. To evaluate the integrity of the blood brain barrier (BBB) in MRL/lpr mice, Western blot for fibronectin, qPCR for iNOS, and immunohistochemical staining for VCAM-1/ICAM-1 were performed. We found preserved BBB permeability in MRL/lpr Fn14KO mice, attributable to reduced brain expression of VCAM-1/ICAM-1 and iNOS. Additionally, administration of Fc-TWEAK intravenously directly increased the leakage of a tracer (dextran-FITC) into brain tissue. Furthermore, MRL/lpr Fn14KO mice displayed reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Finally, we found that MRL/lpr Fn14KO mice manifested reduced neuron degeneration and hippocampal gliosis. Our studies indicate that TWEAK/Fn14 interactions play an important role in the pathogenesis of NPSLE by increasing the accumulation of inflammatory cells in the choroid plexus, disrupting BBB integrity, and increasing neuronal damage, suggesting a novel target for therapy in this disease.

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

“…Major histopathological brain findings in the MRL/lpr strain are immune cell infiltration, compromised blood brain barrier integrity, and brain cell apoptosis [2, 20]. To investigate whether GW2580 treatment affects these histopathological characteristics, cellular infiltrates were observed on H&E stained slides, and albumin was used as a tracer to detect BBB leakage.…”

“…These cytokines can all be released by activated microglia, and additionally may modulate microglia activity. Activated microglia can be found in both human and murine lupus brains [19, 20]. As the major immune effector cell in the brain, it has been surmised that microglia may be relevant to NPSLE pathogenesis.…”

Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice

“…There is increasing recognition of the relevance of TWEAK to the pathogenesis of neurologic disease including NPSLE (Stock et al, 2013; Wen et al, 2015; Wen et al, 2013), EAE (Desplat-Jego et al, 2002), and ischemic stroke (Zhang et al, 2007). We report here that Fc-TWEAK given by ICV injection can induce significant depression-like behavior and learning/memory deficits in non-autoimmune mice.…”

The role of B cells and autoantibodies in neuropsychiatric lupus

“…One prominent histopathological feature in the brains of MRL/lpr mice is gross leukocytic infiltration. By 4 months of age, infiltrates occupy the choroid plexus of the third and fourth ventricles, as well as the periventricular regions adjacent to these ventricles, while isolated leukocytes are observed in the lateral ventricle [27, 28]. The infiltrating population is mixed, predominantly composed of B and T lymphocytes, as well as macrophages [27, 28].…”

“…By 4 months of age, infiltrates occupy the choroid plexus of the third and fourth ventricles, as well as the periventricular regions adjacent to these ventricles, while isolated leukocytes are observed in the lateral ventricle [27, 28]. The infiltrating population is mixed, predominantly composed of B and T lymphocytes, as well as macrophages [27, 28]. Although the appearance of extensive infiltrates in the CNS coincides with the peak of anti-dsDNA autoantibody titers at 4 months of age [27], cellular infiltration in the brains of MRL/lpr mice persists after bone marrow transplantation from healthy control background matched (MRL/mpj) mice [14], indicating that peripheral immune dysregulation may be associated with, but not a direct cause of, the cellular infiltration in the brain.…”