Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL.
Here, we provide evidence for a detrimental role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in neural death in T cell-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Clinical severity and neuronal apoptosis in brainstem motor areas were substantially reduced upon brain-specific blockade of TRAIL after induction of EAE through adoptive transfer of encephalitogenic T cells. Furthermore, TRAIL-deficient myelin-specific lymphocytes showed reduced encephalitogenicity when transferred to wild-type mice. Conversely, intracerebral delivery of TRAIL to animals with EAE increased clinical deficits, while naive mice were not susceptible to TRAIL. Using organotypic slice cultures as a model for living brain tissue, we found that neurons were susceptible to TRAIL-mediated injury induced by encephalitogenic T cells. Thus, in addition to its known immunoregulatory effects, the death ligand TRAIL contributes to neural damage in the inflamed brain.
Aktas
Orhan
O
Institute of Neuroimmunology, Neuroscience Research Center, Charité, Humboldt-University, 10098 Berlin, Germany.
Smorodchenko
Alina
A
Brocke
Stefan
S
Infante-Duarte
Carmen
C
Schulze Topphoff
Ulf
U
Vogt
Johannes
J
Prozorovski
Timour
T
Meier
Susanne
S
Osmanova
Venera
V
Pohl
Elena
E
Bechmann
Ingo
I
Nitsch
Robert
R
Zipp
Frauke
F
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis; D009474:Neurons / Q000276:immunology / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha