A thrombin-PAR1/2 feedback loop amplifies thromboinflammatory endothelial responses to the viral RNA analogue poly(I:C).
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
13 07 2021
13 07 2021
Historique:
received:
25
01
2020
accepted:
12
04
2021
entrez:
9
7
2021
pubmed:
10
7
2021
medline:
24
7
2021
Statut:
ppublish
Résumé
Activation of blood coagulation and endothelial inflammation are hallmarks of respiratory infections with RNA viruses that contribute significantly to the morbidity and mortality of patients with severe disease. We investigated how signaling by coagulation proteases affects the quality and extent of the response to the TLR3-ligand poly(I:C) in human endothelial cells. Genome-wide RNA profiling documented additive and synergistic effects of thrombin and poly(I:C) on the expression level of many genes. The most significantly active genes exhibiting synergistic induction by costimulation with thrombin and poly(I:C) included the key mediators of 2 critical biological mechanisms known to promote endothelial thromboinflammatory functions: the initiation of blood coagulation by tissue factor and the control of leukocyte trafficking by the endothelial-leukocyte adhesion receptors E-selectin (gene symbol, SELE) and VCAM1, and the cytokines and chemokines CXCL8, IL-6, CXCL2, and CCL20. Mechanistic studies have indicated that synergistic costimulation with thrombin and poly(I:C) requires proteolytic activation of protease-activated receptor 1 (PAR1) by thrombin and transactivation of PAR2 by the PAR1-tethered ligand. Accordingly, a small-molecule PAR2 inhibitor suppressed poly(I:C)/thrombin-induced leukocyte-endothelial adhesion, cytokine production, and endothelial tissue factor expression. In summary, this study describes a positive feedback mechanism by which thrombin sustains and amplifies the prothrombotic and proinflammatory function of endothelial cells exposed to the viral RNA analogue, poly(I:C) via activation of PAR1/2.
Identifiants
pubmed: 34242391
pii: S2473-9529(21)00356-6
doi: 10.1182/bloodadvances.2021004360
pmc: PMC8288670
doi:
Substances chimiques
RNA, Viral
0
Receptor, PAR-1
0
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2760-2774Subventions
Organisme : NHLBI NIH HHS
ID : R15 HL127636
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
Références
TH Open. 2020 Nov 23;4(4):e376-e382
pubmed: 33244512
Blood. 2013 Nov 14;122(20):3415-22
pubmed: 24092932
Cytokine. 2005 Mar 21;29(6):256-69
pubmed: 15749026
Thromb Res. 2019 May;177:91-101
pubmed: 30861432
Mol Pharmacol. 2016 May;89(5):606-14
pubmed: 26957205
Arterioscler Thromb Vasc Biol. 2019 Jan;39(1):13-24
pubmed: 30580574
Cell. 2020 May 14;181(4):905-913.e7
pubmed: 32333836
Cell Mol Immunol. 2016 Jul;13(4):432-42
pubmed: 27041635
Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23618-23624
pubmed: 31712416
J Cell Physiol. 2014 Sep;229(9):1292-300
pubmed: 24477600
Blood. 2003 Apr 15;101(8):3042-8
pubmed: 12506026
J Biol Chem. 2004 Nov 5;279(45):46678-85
pubmed: 15339908
Lancet. 2020 May 2;395(10234):1417-1418
pubmed: 32325026
Emerg Microbes Infect. 2020 Dec;9(1):469-473
pubmed: 32102625
J Biol Chem. 2004 Aug 20;279(34):36142-7
pubmed: 15201277
J Thromb Haemost. 2020 Jun;18(6):1421-1424
pubmed: 32271988
J Med Chem. 2010 Oct 28;53(20):7428-40
pubmed: 20873792
Thromb Res. 2020 Jul;191:148-150
pubmed: 32381264
Blood. 2007 Nov 1;110(9):3245-52
pubmed: 17660379
Circ Res. 2009 Mar 27;104(6):742-9
pubmed: 19213954
PLoS One. 2012;7(2):e31229
pubmed: 22359579
Thromb Res. 2016 Jun;142:44-51
pubmed: 27131284
Blood. 1987 Aug;70(2):490-3
pubmed: 3607285
Blood. 2016 Jul 14;128(2):169-77
pubmed: 27127302
J Thromb Thrombolysis. 2014 Jan;37(1):45-55
pubmed: 24241912
J Physiol. 2016 Dec 15;594(24):7267-7307
pubmed: 27730645
Circ Res. 2020 Jul 31;127(4):571-587
pubmed: 32586214
Mol Cancer Res. 2004 Jul;2(7):395-402
pubmed: 15280447
Circulation. 2019 Jan 29;139(5):620-635
pubmed: 30586737
Circ Res. 2010 Aug 20;107(4):501-11
pubmed: 20558821
Blood. 1998 Aug 15;92(4):1259-67
pubmed: 9694714
J Biol Chem. 1993 Jan 5;268(1):421-9
pubmed: 7678000
Am J Physiol Lung Cell Mol Physiol. 2019 Nov 1;317(5):L615-L624
pubmed: 31461311
PLoS One. 2016 Aug 09;11(8):e0160875
pubmed: 27504984
Front Biosci (Landmark Ed). 2018 Jan 1;23:1060-1081
pubmed: 28930589
J Immunol. 2015 Aug 15;195(4):1732-43
pubmed: 26136425
J Pathol. 2004 Jun;203(2):631-7
pubmed: 15141377
Circulation. 2004 Nov 2;110(18):2903-9
pubmed: 15505101
J Vasc Surg. 2020 Dec;72(6):1864-1872
pubmed: 32360679
ACS Med Chem Lett. 2018 Dec 03;10(1):121-126
pubmed: 30655958
Intensive Care Med. 2020 Jun;46(6):1089-1098
pubmed: 32367170
Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):41-53
pubmed: 14551154
J Surg Res. 2011 Aug;169(2):319-27
pubmed: 20451919
J Biol Chem. 2005 Jun 10;280(23):22172-80
pubmed: 15817447
Blood. 2016 Jun 23;127(25):3260-9
pubmed: 27114461
Blood. 2009 Jan 15;113(3):714-22
pubmed: 18971420
Exp Cell Res. 2019 Oct 1;383(1):111505
pubmed: 31326389
J Biol Chem. 2005 May 20;280(20):19808-14
pubmed: 15769747
Arterioscler Thromb Vasc Biol. 2020 Aug;40(8):1818-1829
pubmed: 32510978
Am J Reprod Immunol. 2016 Jul;76(1):29-37
pubmed: 27108773
Elife. 2017 Jun 06;6:
pubmed: 28585919
Nat Rev Immunol. 2020 Jul;20(7):389-391
pubmed: 32439870
J Clin Virol. 2020 Jun;127:104362
pubmed: 32305883
J Thromb Haemost. 2021 Apr;19(4):1103-1111
pubmed: 33346953
FASEB J. 2005 Nov;19(13):1914-6
pubmed: 16172186
J Thromb Haemost. 2020 Jun;18(6):1511-1513
pubmed: 32293083
Nat Rev Immunol. 2007 Sep;7(9):678-89
pubmed: 17717539
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Res Pract Thromb Haemost. 2018 May 24;2(3):549-557
pubmed: 30046760
Circulation. 1997 Oct 7;96(7):2262-71
pubmed: 9337199
J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973
pubmed: 32311448
G3 (Bethesda). 2019 Jul 9;9(7):2089-2096
pubmed: 31088905
Nat Immunol. 2007 Dec;8(12):1303-12
pubmed: 17965715
J Thromb Haemost. 2020 May;18(5):1094-1099
pubmed: 32220112
J Neuroimmunol. 2012 Apr;245(1-2):48-55
pubmed: 22381244
Trends Cardiovasc Med. 2003 Apr;13(3):93-101
pubmed: 12691672
Nat Med. 2020 Jul;26(7):1017-1032
pubmed: 32651579
Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1368-1380
pubmed: 29622563
Thromb Res. 2020 Dec;196:483-485
pubmed: 33091700
Blood. 2014 Mar 20;123(12):e22-36
pubmed: 24501219
J Infect Dis. 2020 Oct 13;222(10):1596-1600
pubmed: 32745172
Arterioscler Thromb Vasc Biol. 2020 Sep;40(9):2033-2044
pubmed: 32657623
J Thromb Haemost. 2012 Aug;10(8):1675-84
pubmed: 22712885
Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):353-362
pubmed: 29284606
N Engl J Med. 2020 May 14;382(20):e60
pubmed: 32343504
Mucosal Immunol. 2013 May;6(3):474-84
pubmed: 22990623
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1535-40
pubmed: 12842839
Am J Physiol Cell Physiol. 2005 Dec;289(6):C1437-47
pubmed: 16079188