Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL

Neuron. 2005 May 5;46(3):421-32. doi: 10.1016/j.neuron.2005.03.018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / immunology
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Brain / immunology
  • Brain / metabolism
  • Brain / pathology*
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Female
  • Flow Cytometry
  • Immunohistochemistry
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Multiple Sclerosis
  • Neurons / immunology
  • Neurons / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha