title: Expression of TWEAK and its receptor Fn14 in the multiple sclerosis brain: implications for inflammatory tissue injury.
abstract: The expression patterns of tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a pleiotropic cytokine with proinflammatory and cell death-inducing activities, and its receptor, fibroblast growth factor-inducible 14 (Fn14), were examined in postmortem brain tissue samples from patients with multiple sclerosis (MS) and controls. Immunohistochemical analysis and real-time reverse transcription-polymerase chain reaction demonstrated that both TWEAK and Fn14 were upregulated in the MS compared with control unaffected brain samples. Perivascular and meningeal macrophages and astrocytes and microglia associated with lesions were identified as the main sources of TWEAK in the MS brains. The highest frequency of TWEAK+ cells was found at edges of chronic active white matter lesions and in subpial cortical lesions inMS cases with abundant meningeal inflammation and ectopic B-cell follicles. Neurons and reactive astrocytes expressing Fn14 were mainly localized in the cerebral cortex in highly infiltrated MS brains. Numerous TWEAK-expressing microglia were associated with the extensive loss of myelin and astrocytosis, neuronal damage, and vascular abnormalities in subpial cortical lesions; this suggests that TWEAK could synergize with other cytotoxic factors diffusing from the inflamed meninges to promote cortical injury. Taken together, these findings indicate that the TWEAK/Fn14 pathway contributes to inflammation and tissue injury and is, therefore, a potential therapeutic target in MS.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Serafini
authors.forename: Roberta
authors.initials: R
authors.lastname: Magliozzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Rosicarelli
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.forename: Francesca
authors.initials: F
authors.lastname: Aloisi
mesh_terms: D001253:Astrocytes / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002536:Cerebral Arteries / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D000074049:Cytokine TWEAK; D004660:Encephalitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D005911:Gliosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008578:Meninges / Q000276:immunology / Q000473:pathology; D017628:Microglia / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors