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

Abstract

Tumor necrosis factor ␣ (TNF-␣) 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-␣ 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 ϩ/Ϫ 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-␣ 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-␣-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-␣ 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-␣ signaling in CNS diseases: a feedback loop integrating TNF-␣, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-␣ mediated neuroprotection in situ and a rationale for therapeutic intervention.

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

“…1a). TNFR1 has been shown to undergo ADAM17-and ADAM8-mediated cleavage, resulting in the release of sTNFR1 ectodomains and generation of a membrane-anchored TNFR1 CTF (38,64). The majority of known ␥-secretase substrates also undergo ectodomain shedding in the extracellular domain as a prerequisite for ␥-secretase-mediated cleavage of the remaining membrane-bound CTF.…”

“…TACE/ADAM17, a member of the A disintegrin and metalloprotease (ADAM) family of transmembrane and secreted proteases, is responsible for ectodomain shedding of TNFR1 (38,39). Recently, it has emerged that several proteins that undergo ectodomain shedding are subsequently cleaved by the ␥-secretase protease (40 -42).…”

Proteomic analysis of muscle affected by motor neuron degeneration: The wobbler mouse model of amyotrophic lateral sclerosis

“…valuable model for many aspects of neurodegeneration, including neuroinflammatory processes [13]. The WR mouse is also widely employed for evaluating novel treatment options to counteract symptoms of ALS [14].…”

1,25-Dihydroxyvitamin D3 Causes ADAM10-Dependent Ectodomain Shedding of Tumor Necrosis Factor Receptor 1 in Vascular Smooth Muscle Cells

“…PMA induces the shedding by activating ADAM17, whereas ionomycin, an agent causing extracellular Ca 21 influx, induces it by activating ADAM10 (Nagano et al, 2004). So far, ADAMs 17 and 8, but not ADAM10, are known to cleave the extracellular domain of TNFR1 (Bell et al, 2007;Bartsch et al, 2010). In most studies, ADAM17 has been identified as a TNFR1 sheddase, but ADAM8 was responsible for shedding of TNFR1 in the isolated primary neurons and microglia stimulated with TNF-a (Bartsch et al, 2010).…”

“…So far, ADAMs 17 and 8, but not ADAM10, are known to cleave the extracellular domain of TNFR1 (Bell et al, 2007;Bartsch et al, 2010). In most studies, ADAM17 has been identified as a TNFR1 sheddase, but ADAM8 was responsible for shedding of TNFR1 in the isolated primary neurons and microglia stimulated with TNF-a (Bartsch et al, 2010). Because ADAM17 cleaves TNFR2 as well as TNFR1 (Saftig and Reiss, 2011), shedding of TNFR1, but not TNFR2 by 1,25D 3 in the present study, suggests that ADAM17 is not the responsible sheddase.…”