Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling.
Toll-like receptor 4
cotinine
microglia
molecular dynamics simulation
myeloid differentiation protein 2
nicotine
Journal
Innovation (Cambridge (Mass.))
ISSN: 2666-6758
Titre abrégé: Innovation (Camb)
Pays: United States
ID NLM: 101771342
Informations de publication
Date de publication:
28 May 2021
28 May 2021
Historique:
received:
26
09
2020
accepted:
27
04
2021
entrez:
24
9
2021
pubmed:
25
9
2021
medline:
25
9
2021
Statut:
epublish
Résumé
Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive substances morphine, cocaine, and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4 (TLR4), here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2 (MD2), an accessory protein of TLR4 that is responsible for ligand recognition. MD2-intrinsic fluorescence titrations, surface plasmon resonance, and competitive displacement binding assays with curcumin (MD2 probe) demonstrated that both nicotine and cotinine targeted the lipopolysaccharide (LPS; TLR4 agonist) binding pocket of MD2 with similar affinities. The cellular thermal shift assay indicated that nicotine binding increased, while cotinine binding decreased, MD2 stability. These biophysical binding results were further supported by
Identifiants
pubmed: 34557761
doi: 10.1016/j.xinn.2021.100111
pii: S2666-6758(21)00036-9
pmc: PMC8454564
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100111Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare that they have no conflict of interest.
Références
J Leukoc Biol. 2007 Oct;82(4):968-74
pubmed: 17609337
Acc Chem Res. 2020 May 19;53(5):1046-1055
pubmed: 32233400
Cell. 2010 Mar 19;140(6):805-20
pubmed: 20303872
Nat Rev Cancer. 2009 Mar;9(3):195-205
pubmed: 19194381
Psychopharmacology (Berl). 2007 Feb;190(3):269-319
pubmed: 16896961
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6325-30
pubmed: 22474354
ALTEX. 2009;26(2):83-94
pubmed: 19565166
FASEB J. 2019 Aug;33(8):9577-9587
pubmed: 31162938
Neural Regen Res. 2020 Jul;15(7):1208-1219
pubmed: 31960800
Langmuir. 2016 Jul 26;32(29):7392-402
pubmed: 27338140
ACS Chem Neurosci. 2019 Aug 21;10(8):3622-3634
pubmed: 31282647
Chemistry. 2017 May 29;23(30):7238-7244
pubmed: 28212459
Mol Psychiatry. 2015 Dec;20(12):1525-37
pubmed: 25644383
Biochem Pharmacol. 1997 Oct 1;54(7):743-53
pubmed: 9353128
Br J Pharmacol. 2016 Mar;173(5):856-69
pubmed: 26603732
CNS Neurosci Ther. 2008 Winter;14(4):266-77
pubmed: 19040552
Nat Protoc. 2014 Sep;9(9):2100-22
pubmed: 25101824
J Chem Inf Model. 2020 Mar 23;60(3):1607-1613
pubmed: 31935095
Cell Res. 2013 Nov;23(11):1270-83
pubmed: 23979021
Int J Biol Sci. 2020 Feb 17;16(8):1288-1302
pubmed: 32210720
Pharmacol Ther. 2012 Mar;133(3):291-8
pubmed: 22119168
Brain Behav Immun. 2019 Nov;82:432-444
pubmed: 31542403
Toxicol Lett. 1999 Sep 20;109(1-2):21-9
pubmed: 10514027
Eur J Neurosci. 2020 Feb;51(3):781-792
pubmed: 31613395
Life Sci. 2003 May 16;72(26):2931-42
pubmed: 12706481
J Med Chem. 2015 Jun 25;58(12):5038-52
pubmed: 26010811
Fitoterapia. 2014 Oct;98:11-21
pubmed: 24972350
FEBS Lett. 2008 Nov 26;582(28):3929-34
pubmed: 18977229
Eur J Neurosci. 2007 Jul;26(1):79-89
pubmed: 17581257
JAMA Psychiatry. 2018 Oct 1;75(10):987-988
pubmed: 30285225
J Chem Inf Model. 2018 Apr 23;58(4):816-825
pubmed: 29518316
J Mol Med (Berl). 2017 Feb;95(2):221-233
pubmed: 27709266
Eur Biophys J. 2011 Dec;40(12):1357-69
pubmed: 21947507