The role of TRAIL/TRAIL receptors in central nervous system pathology.
Initially, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) aroused major interest due to its preferential toxic effect against malignant cells. However, subsequent studies revealed that the TRAIL system, comprising the family of signal-mediating and decoy TRAIL receptors, (i) can also induce death of non-transformed cells, (ii) has potent immunoregulatory functions, and (iii) exhibits a unique expression pattern in the central nervous system (CNS). Indeed, TRAIL is not expressed within the human brain, while apoptosis-inducing TRAIL receptors are found differently distributed on neurons, oligodendrocytes, and astrocytes. These findings rule out a major contribution of TRAIL to the so-called "immune privilege" of the brain, in which local inflammation is limited, although such a role has previously been suggested for the CD95 (Fas) ligand belonging to the same TNF/nerve growth factor (NGF) family. If, under pathologic circumstances, the CNS is inflamed, immune cells such as macrophages and T cells upregulate TRAIL upon activation and use this death ligand as a weapon, not only against tumor cells but also against neurons and oligodendrocytes within the inflamed CNS. In parallel, a profound immunoregulatory impact of TRAIL on activation and proliferation of encephalitogenic T cells outside the brain has also been shown. Thus, these studies have uncovered a complex action of TRAIL on CNS pathology, indicating the possible value of targeted manipulation of the TRAIL system for the treatment of inflammatory neurodegenerative diseases such as multiple sclerosis.
Aktas
Orhan
O
Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, Neuroscience Research Center NWFZ 2680, Charite, Universitatsmedizin Berlin, Charite Campus Mitte, Berlin, Germany.
Schulze-Topphoff
Ulf
U
Zipp
Frauke
F
D002493:Central Nervous System Diseases / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand