title: 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.
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Christopher Holden
authors.initials: CH
authors.lastname: Chen
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Stock
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Doerner
authors.affiliation: Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: chaim.putterman@einstein.yu.edu.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000139:chemically induced*; D000074049:Cytokine TWEAK; D003863:Depression / Q000139:chemically induced*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism; D005260:Female; D007276:Injections, Intraventricular; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
keywords: Neuropsychiatric lupus; TWEAK