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

Abstract

Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.

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

“…To evaluate the therapeutic effect of GW2580 administration on cognitive function, an object placement (spatial memory) test was conducted. Generally, animals possess an innate preference to explore objects in novel locations, and a preference score of more than 53% indicates preserved memory [26]. However, mice treated with GW2580 exhibited a preference score of 44.1% ± 6.4 %, suggesting that they are incapable of recalling the original placement of the object, similar to the control treated animals (52.3% ± 6.6%) (p=NS).…”

“…Cytokine dysregulation has been proven to be directly associated with depression by numerous studies [33, 36]. Intracerebroventricular injection of microglia-derived cytokines such as TWEAK and IL-6 directly result in depression-like behavior in vivo [26, 37]. In addition, systemic inflammatory mediators may also induce negative behavior outcomes by accessing the brain via the BBB, or directly acting on the vagus nerve [38].…”

“…A standardized object placement (OP) test was employed to assess spatial recognition memory, as described [26, 27]. In brief, mice were given 5 minutes to explore two identical objects which had been placed in different locations within a cage.…”

The blood brain barrier and neuropsychiatric lupus: new perspectives in light of advances in understanding the neuroimmune interface

“…The cytokine TNF-like weak inducer of apoptosis (TWEAK) has been found to play a role in the pathogenesis of NPSLE (and other neuropathologies, such as stroke and EAE) [16, 61–65]. Evaluation of human cerebral microvascular endothelium in culture found that TWEAK signaling induced increased expression of cytokines, including IL-6 and IL-8, as well as ICAM-1 and E-selectin [66].…”

The role of B cells and autoantibodies in neuropsychiatric lupus

“…Autoantibody deposition leads to neurotoxicity and glial cell activation, which can in turn produce abundant, locally enriched cytokines in the CNS, ultimately resulting in behavioral abnormalities. Further, elevated cytokines within the CNS, such as TWEAK, are able to induce neuropsychiatric manifestations directly by mediating inflammatory responses of brain resident cells [8]. It should also be noted that some systemically elevated cytokines can alter behavior directly through the vagus nerve, without ever passing through the BBB [9].…”