cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.
Human RPE cells
Inflammatory cytokines
Ischemia–reperfusion
Neuroprotectin D1
Neuroprotection
Non-conventional cytokine
Retinal pigment epithelial cells
Stroke
Uncompensated oxidative stress
Wnt5a promoter
Journal
Cellular and molecular neurobiology
ISSN: 1573-6830
Titre abrégé: Cell Mol Neurobiol
Pays: United States
ID NLM: 8200709
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
received:
14
04
2022
accepted:
10
05
2022
pubmed:
28
5
2022
medline:
15
3
2023
entrez:
27
5
2022
Statut:
ppublish
Résumé
Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke.
Identifiants
pubmed: 35622188
doi: 10.1007/s10571-022-01231-6
pii: 10.1007/s10571-022-01231-6
pmc: PMC10006067
doi:
Substances chimiques
Docosahexaenoic Acids
25167-62-8
protectin D1
0
Wnt-5a Protein
0
WNT5A protein, human
0
Frizzled Receptors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1077-1096Subventions
Organisme : NEI NIH HHS
ID : R01 EY005121
Pays : United States
Organisme : NEI NIH HHS
ID : R01EY005121
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS104117
Pays : United States
Organisme : NINDS NIH HHS
ID : R01NS104117
Pays : United States
Organisme : NINDS NIH HHS
ID : R01NS104117
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109221
Pays : United States
Organisme : NEI NIH HHS
ID : R01EY005121
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
Références
J Biol Chem. 2014 Jul 25;289(30):21028-39
pubmed: 24891513
Arthritis Rheum. 2001 Apr;44(4):772-81
pubmed: 11315916
Cell Signal. 2014 Feb;26(2):260-7
pubmed: 24269653
J Cell Mol Med. 2008 Dec;12(6B):2731-53
pubmed: 18266980
J Biol Chem. 2009 Jun 26;284(26):17877-82
pubmed: 19403949
J Immunol. 2010 Jul 15;185(2):1274-82
pubmed: 20554957
Mol Brain. 2012 Jan 04;5:1
pubmed: 22217152
Mol Cell Biol. 2016 Aug 22;36(21):2728-2741
pubmed: 27550808
Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24317-24325
pubmed: 31712409
J Biol Chem. 2012 Jan 6;287(2):1588-99
pubmed: 22128168
Bioinformatics. 1999 Jul-Aug;15(7-8):622-30
pubmed: 10487870
Cell Death Differ. 2017 Jun;24(6):1091-1099
pubmed: 28430183
Trends Neurosci. 2006 May;29(5):263-71
pubmed: 16580739
Nucleic Acids Res. 2007 Jan;35(Database issue):D137-40
pubmed: 17202159
PLoS One. 2016 Mar 15;11(3):e0151392
pubmed: 26978652
Transl Stroke Res. 2011 Mar;2(1):33-41
pubmed: 21423332
Sci Rep. 2015 Jun 01;5:10536
pubmed: 26030277
Bioinformatics. 2002 Nov;18(11):1427-31
pubmed: 12424112
J Biol Chem. 2012 Jul 6;287(28):23726-39
pubmed: 22511762
Biochem J. 2007 Mar 15;402(3):515-23
pubmed: 17117926
Anal Biochem. 1984 Apr;138(1):141-3
pubmed: 6731838
Development. 2014 Apr;141(8):1757-66
pubmed: 24715464
Sci Rep. 2015 Jan 27;5:8042
pubmed: 25622531
Front Cardiovasc Med. 2020 Nov 19;7:567837
pubmed: 33330641
Cells. 2019 Sep 10;8(9):
pubmed: 31510045
J Bone Miner Res. 2012 Mar;27(3):575-85
pubmed: 22162112
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21164-9
pubmed: 21084636
Cancer Res. 2017 Feb 15;77(4):996-1007
pubmed: 28011620
Int J Chron Obstruct Pulmon Dis. 2020 Oct 23;15:2653-2662
pubmed: 33122903
Invest Ophthalmol Vis Sci. 2007 Nov;48(11):4866-81; biography 4864-5
pubmed: 17962433
Neural Plast. 2016;2016:9839348
pubmed: 27688915
J Cell Physiol. 2015 Jun;230(6):1170-80
pubmed: 25336320
PLoS Biol. 2006 Apr;4(4):e115
pubmed: 16602827
Cell Death Differ. 2015 Aug;22(8):1363-77
pubmed: 25633199
Science. 2003 Sep 5;301(5638):1391-4
pubmed: 12958364
Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19473-8
pubmed: 19901340
J Biol Chem. 2015 Mar 13;290(11):6789-98
pubmed: 25605717
Nat Methods. 2012 Jun 28;9(7):683-9
pubmed: 22743773
Cell Res. 2016 Feb;26(2):262-5
pubmed: 26337801
Front Neurol. 2021 Apr 22;12:621555
pubmed: 33967935
Front Cell Neurosci. 2017 Sep 29;11:281
pubmed: 29033786
Acta Biochim Biophys Sin (Shanghai). 2011 Oct;43(10):745-56
pubmed: 21903638
Cell Adh Migr. 2017 Jan 2;11(1):24-38
pubmed: 27159116
J Immunol. 2014 May 1;192(9):4386-97
pubmed: 24706725
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8491-6
pubmed: 15152078
Cell Mol Life Sci. 2018 Mar;75(5):785-795
pubmed: 28913633
DNA Cell Biol. 2012 Nov;31(11):1585-97
pubmed: 23046419
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Nat Cell Biol. 2012 Oct;14(10):1036-45
pubmed: 22983114
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13152-7
pubmed: 17670936
Cell. 2017 Jun 1;169(6):985-999
pubmed: 28575679
Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):504-10
pubmed: 18174455
Annu Rev Cell Dev Biol. 2021 Oct 6;37:369-389
pubmed: 34196570