title: Tumor necrosis factor-alpha (TNF-alpha) regulates shedding of TNF-alpha receptor 1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated feedback loop in neuroprotection.
abstract: Tumor necrosis factor alpha (TNF-alpha) is a potent cytokine in neurodegenerative disorders, but its precise role in particular brain disorders is ambiguous. In motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), TNF-alpha causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in affected brain regions, spinal cord, and brainstem. The functional role of A8 during MN degeneration in the wobbler CNS was investigated by crossing WR with A8-deficient mice: a severely aggravated neuropathology was observed for A8-deficient WR compared with WR A8(+/-) mice, judged by drastically reduced survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in the forelimbs, and terminal akinesis. In vitro protease assays using soluble A8 indicated specific cleavage of a TNF-alpha receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmed in situ, because levels of soluble TNF-R1 were increased in spinal cords of standard WR compared with wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and microglia, TNF-alpha-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-alpha showed higher toxicity for cultured neurons from A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 shedding by A8 is neuroprotective. Our results indicate an essential role for ADAM8 in modulating TNF-alpha signaling in CNS diseases: a feedback loop integrating TNF-alpha, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-alpha mediated neuroprotection in situ and a rationale for therapeutic intervention.
authors.affiliation: Pharmaceutical Science Research Division, King's College London, London, United Kingdom. jorg.bartsch@kcl.ac.uk
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Bartsch
authors.forename: Dirk
authors.initials: D
authors.lastname: Wildeboer
authors.forename: Garrit
authors.initials: G
authors.lastname: Koller
authors.forename: Silvia
authors.initials: S
authors.lastname: Naus
authors.forename: Andrea
authors.initials: A
authors.lastname: Rittger
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Moss
authors.forename: Yuji
authors.initials: Y
authors.lastname: Minai
authors.forename: Harald
authors.initials: H
authors.lastname: Jockusch
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009133:Muscular Atrophy / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D051722:ADAM Proteins; C489402:Adam8 protein, mouse
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