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.
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.
Bartsch
Jörg W
JW
Pharmaceutical Science Research Division, King's College London, London, United Kingdom. jorg.bartsch@kcl.ac.uk
Wildeboer
Dirk
D
Koller
Garrit
G
Naus
Silvia
S
Rittger
Andrea
A
Moss
Marcia L
ML
Minai
Yuji
Y
Jockusch
Harald
H
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
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
Curr Opin Immunol. 2000 Aug;12(4):479-86
10899034
J Neuroimmune Pharmacol. 2007 Jun;2(2):140-53
18040839
J Immunol. 1994 May 15;152(10):5070-6
7513728
Curr Pharm Des. 2009;15(20):2272-81
19601829
Genomics. 1992 May;13(1):39-43
1349581
Science. 1994 Aug 19;265(5175):1107-10
8066451
Neurobiol Dis. 2008 Mar;29(3):465-76
18201889
Biol Chem. 2006 Mar;387(3):337-46
16542157
Science. 1998 Nov 13;282(5392):1281-4
9812885
Cell. 1999 Apr 2;97(1):133-44
10199409
J Comp Neurol. 2009 Jan 10;512(2):243-55
19003792
J Immunol. 2003 Dec 15;171(12):6814-9
14662887
Dev Neurosci. 1988;10(3):190-8
3142758
J Biol Chem. 2002 Dec 13;277(50):48210-9
12372841
Medicine (Baltimore). 2002 Sep;81(5):349-68
12352631
Neurobiol Aging. 2003 Dec;24(8):1063-70
14643377
Nature. 1997 Feb 20;385(6618):729-33
9034190
J Neurosci. 2000 Nov 1;20(21):7964-71
11050116
Biochemistry. 2002 Jul 30;41(30):9462-9
12135369
Nature. 1997 Feb 20;385(6618):733-6
9034191
J Biol Chem. 2000 May 12;275(19):14608-14
10799547
Rev Neurosci. 2008;19(4-5):341-61
19145989
Dev Dyn. 2005 Jan;232(1):221-31
15580619
Science. 2002 May 31;296(5573):1634-5
12040173
Neuroreport. 1999 Nov 8;10(16):3411-6
10599854
Brain Behav Immun. 2007 Mar;21(3):281-9
17275255
J Immunol. 1997 Apr 15;158(8):3869-73
9103455
Ann N Y Acad Sci. 2008 Oct;1139:318-30
18991877
J Neurosci. 2006 Nov 1;26(44):11397-402
17079668
J Biol Chem. 2003 Jun 6;278(23):20555-64
12663667
Nat Genet. 2005 Nov;37(11):1213-5
16244655
FEBS J. 2010 Jan;277(1):22-9
19843173
J Biol Chem. 2004 Apr 16;279(16):16083-90
14761956
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6185-90
18413601
Int J Biochem Cell Biol. 2002 Jan;34(1):1-5
11733179
J Exp Med. 2004 Aug 2;200(3):367-76
15289505
J Clin Invest. 2002 Aug;110(4):515-26
12189246