Tumor Necrosis Factor-α (TNF-α) Regulates Shedding of TNF-α Receptor 1 by the Metalloprotease-Disintegrin ADAM8: Evidence for a Protease-Regulated Feedback Loop in Neuroprotection

• DOI: 10.1523/jneurosci.1520-10.2010
• Publication Date: 2010-09-08T16:47:56Z
• Authors: Jörg W. Bartsch; Dirk Wildeboer; Garrit Koller; Silvia Naus; Andrea Rittger; Marcia L. Moss; Yuji Minai; Harald Jockusch
• Keywords: Central Nervous System; Mice, Knockout; 0301 basic medicine; 0303 health sciences; Dose-Response Relationship, Drug; 610; Membrane Proteins; Cell Count; Enzyme-Linked Immunosorbent Assay; Nerve Tissue Proteins; Neurodegenerative Diseases; Kaplan-Meier Estimate; Mice, Inbred C57BL; ADAM Proteins; Mice; Muscular Atrophy; 03 medical and health sciences; Animals, Newborn; Gene Expression Regulation; Antigens, CD; Animals; Humans; Leukocyte Common Antigens; Neuroglia

Tumor necrosis factor α (TNF-α) 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-α 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 vitroprotease assays using soluble A8 indicated specific cleavage of a TNF-α receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmedin 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-α-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-α 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-α signaling in CNS diseases: a feedback loop integrating TNF-α, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-α mediated neuroprotectionin situand a rationale for therapeutic intervention.