Background/Purpose:

Neuropsychiatric lupus (NPSLE) is a common disease manifestation in lupus patients; however, the underlying mechanisms are not fully understood. TWEAK is a cytokine member of the TNF superfamily; the TWEAK receptor, Fn14, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. Previously, we had found that Fn14 knockout MRL/lpr lupus mice have significantly attenuated neuropsychiatric manifestations. To establish whether this improvement in disease is secondary to inhibition of TWEAK-Fn14 signaling within the CNS rather than in the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed short term intra-cerebroventricular injections (ICV) of Fc-TWEAK to C57Bl6/J (B6) mice.

Methods:

ICV injection of Fc-TWEAK (2 μg, n=12) or isotype control (P1.17, 2 μg, n=11) was conducted twice a week in B6 mice at 8 weeks of age for a total of 5 injections, according to the following stereotaxic coordinates: anteroposterior: -0.34 mm, mediolateral: -1.0 mm; dorsal ventricular: 2mm.  Three days after the last injection, neurobehavioral tests including open field, object placement, object recognition, anhedonia, and forced swim were performed, after which the mice were sacrificed. To evaluate whether ICV administration of Fc-TWEAK modulates changes in blood brain barrier (BBB) integrity, extravascular fibronectin, aquaporin-4, and iNOS expression were evaluated by Western blot, immunofluorescence staining and qRT-PCR, respectively. Complement activation was assessed by measuring the expression of C3 by qRT-PCR and Western blot. TUNEL staining was employed to analyze for apoptosis in brain cells.

Results:

We found that Fc-TWEAK injected non-autoimmune mice developed significant depressive-like behavior and cognitive dysfunction (impaired spatial memory). Inflammatory mediators associated with lupus brain disease, including MCP-1, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased BBB permeability, as demonstrated by increased fibronectin deposition and reduced aquaporin-4 expression in the brain of Fc-TWEAK treated mice. Finally, mice injected with Fc-TWEAK exhibited increased apoptotic cell death in the cortex and hippocampus. 

Conclusion:

TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive deficits by acting within the CNS to enhance production of inflammatory mediators, promote permeability 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 neuropsychiatric manifestations in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intracerebroventricular-tweak-tnf-like-weak-inducer-of-apoptosis-induces-depressive-like-behavior-and-cognitive-dysfunction-in-non-autoimmune-mice/