Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice |
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| Affiliation: | 1. The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA;2. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA;3. Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA;4. Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA;1. Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, 68 Zhong Shan Road, Wuxi 214002, Jiangsu Province, China;2. Department of Hospital Infection-Control, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi, Jiangsu Province, China;1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA;2. Institute for Drug and Alcohol Studies, Virginia Commonwealth University, USA;1. Department of Neuro-Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, Netherlands;1. Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy;2. Azienda Ospedaliero Universitaria “Ospedali Riuniti”, Ancona, Italy;1. Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy;2. Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy;1. Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Moscow Region, Russia;2. Biophysics Department, “Dubna” University, 19 Universitetskaya St., 141980 Dubna, Moscow Region, Russia;3. Academy of Sciences of Moldova, Chișinău, Moldova;4. Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia;5. Zakusov Institute of Pharmacology, Moscow, Russia;6. Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia |
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| 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. |
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| Keywords: | Neuropsychiatric lupus TWEAK |
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