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

Bartsch JW, Wildeboer D, Koller G, Naus S, Rittger A, Moss ML, Minai Y, Jockusch H (2010)
J Neurosci 30(36): 12210-12218.

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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 WRA8(+/-) 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.
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Bartsch JW, Wildeboer D, Koller G, et al. 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. J Neurosci. 2010;30(36):12210-12218.
Bartsch, J. W., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M. L., Minai, Y., et al. (2010). 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. J Neurosci, 30(36), 12210-12218.
Bartsch, J. W., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M. L., Minai, Y., and Jockusch, H. (2010). 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. J Neurosci 30, 12210-12218.
Bartsch, J.W., et al., 2010. 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. J Neurosci, 30(36), p 12210-12218.
J.W. Bartsch, et al., “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”, J Neurosci, vol. 30, 2010, pp. 12210-12218.
Bartsch, J.W., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M.L., Minai, Y., Jockusch, H.: 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. J Neurosci. 30, 12210-12218 (2010).
Bartsch, Joerg W., Wildeboer, Dirk, Koller, Garrit, Naus, Silvia, Rittger, Andrea, Moss, Marcia L., Minai, Yuji, and Jockusch, Harald. “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”. J Neurosci 30.36 (2010): 12210-12218.
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