TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice.
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.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Jing
J
Wen
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Jessica
J
Doerner
Department of Neuropathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Karen
K
Weidenheim
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yumin
Y
Xia
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ariel
A
Stock
Jounce Therapeutics, Cambridge, MA 02138, USA.
Jennifer S
JS
Michaelson
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Kuti
K
Baruch
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Aleksandra
A
Deczkowska
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Maria
M
Gulinello
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Michal
M
Schwartz
Department of Immunology, Biogen Idec, Cambridge, MA 02142, USA.
Linda C
LC
Burkly
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Division of Rheumatology and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: chaim.putterman@einstein.yu.edu.
Chaim
C
Putterman
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002831:Choroid Plexus / Q000503:physiopathology; D003071:Cognition; D003176:Complement C3 / Q000276:immunology; D015934:Complement C4a / Q000276:immunology; D003183:Complement C6 / Q000276:immunology; D000074049:Cytokine TWEAK; D003863:Depression / Q000235:genetics; D004195:Disease Models, Animal; D005911:Gliosis / Q000235:genetics; D007074:Immunoglobulin G / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D010539:Permeability; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis
D003176:Complement C3; D003183:Complement C6; D000074049:Cytokine TWEAK; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C569043:Tjp1 protein, mouse; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D019010:Vascular Cell Adhesion Molecule-1; D062826:Zonula Occludens-1 Protein; D018799:Intercellular Adhesion Molecule-1; D015934:Complement C4a
Fn14; Neuropsychiatric lupus (NPSLE); Systemic lupus erythematous (SLE); TWEAK