Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.
Toll-like receptor 3
aortic valve disease
biglycan
extracellular matrix
osteogenesis
proteins
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
16 05 2023
16 05 2023
Historique:
pmc-release:
16
05
2024
medline:
17
5
2023
pubmed:
5
4
2023
entrez:
4
4
2023
Statut:
ppublish
Résumé
Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan ( Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.
Sections du résumé
BACKGROUND
Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling.
METHODS
Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (
RESULTS
Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that
CONCLUSIONS
This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.
Identifiants
pubmed: 37013819
doi: 10.1161/CIRCULATIONAHA.122.063481
pmc: PMC10192061
mid: NIHMS1884895
doi:
Substances chimiques
Biglycan
0
Toll-Like Receptor 3
0
TLR3 protein, human
0
TLR3 protein, mouse
0
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
1518-1533Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL128550
Pays : United States
Références
Cell. 1997 May 30;89(5):747-54
pubmed: 9182762
Cardiovasc Res. 2016 Feb 1;109(2):331-43
pubmed: 26676850
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Science. 2005 Jul 22;309(5734):581-5
pubmed: 15961631
Eur J Biochem. 2002 Aug;269(15):3688-96
pubmed: 12153565
Genome Biol. 2014;15(12):550
pubmed: 25516281
Science. 2000 Sep 1;289(5484):1501-4
pubmed: 10968779
Bioinformatics. 2014 Jun 15;30(12):1771-3
pubmed: 24532726
Science. 2007 Sep 14;317(5844):1522-7
pubmed: 17872438
J Med Genet. 2020 Jul;57(7):475-478
pubmed: 31772029
Nat Rev Dis Primers. 2016 Mar 03;2:16006
pubmed: 27188578
J Clin Invest. 2021 Jan 4;131(1):
pubmed: 33393505
Ann Neurol. 1984 Jan;15(1):49-54
pubmed: 6712192
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9445-9
pubmed: 12082181
Genetics. 2015 Aug;200(4):1051-60
pubmed: 26092718
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Dev Biol. 2014 Jan 1;385(1):67-82
pubmed: 24161523
J Am Coll Cardiol. 2019 May 7;73(17):2150-2162
pubmed: 31047003
N Engl J Med. 2013 Feb 7;368(6):503-12
pubmed: 23388002
J Biol Chem. 2004 Mar 26;279(13):12542-50
pubmed: 14729660
J Am Coll Cardiol. 2006 Feb 21;47(4):850-5
pubmed: 16487855
Circulation. 2009 Feb 17;119(6):880-90
pubmed: 19221231
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Circulation. 2021 Jun 22;143(25):2428-2430
pubmed: 34152795
Nature. 2014 Nov 27;515(7528):523-7
pubmed: 25363762
Nat Genet. 2016 Jul;48(7):817-20
pubmed: 27270105
Nat Immunol. 2010 May;11(5):373-84
pubmed: 20404851
Nucleic Acids Res. 2011 Jan;39(Database issue):D712-7
pubmed: 21071422
Circulation. 2006 Nov 7;114(19):2065-9
pubmed: 17075015
Biotech Histochem. 2007 Feb;82(1):23-8
pubmed: 17510811
Proteins. 2005 Jan 1;58(1):134-43
pubmed: 15495260
Front Cardiovasc Med. 2021 Oct 29;8:687210
pubmed: 34778386
Nature. 2002 Apr 18;416(6882):744-9
pubmed: 11961557
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W233-8
pubmed: 18442991
J Vis Exp. 2017 Feb 14;(120):
pubmed: 28287525
Circ Res. 2021 Apr 30;128(9):1344-1370
pubmed: 33914601
J Biol Chem. 2010 Nov 19;285(47):36836-41
pubmed: 20861016
Circulation. 2006 Dec 5;114(23):2482-9
pubmed: 17116765
Circulation. 2008 Sep 16;118(12):1276-84
pubmed: 18765390
Int J Cardiol. 2012 Jun 28;158(1):18-25
pubmed: 21247641
JAKSTAT. 2013 Jul 1;2(3):e23930
pubmed: 24069548
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Bioinformatics. 2002 Jan;18(1):207-8
pubmed: 11836235
Sci Rep. 2016 Sep 29;6:34515
pubmed: 27682821
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
J Comput Chem. 2010 Jan 15;31(1):133-43
pubmed: 19421996
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1631-1636
pubmed: 28137840
J Am Heart Assoc. 2015 Oct 27;4(10):e002440
pubmed: 26508745
J Allergy Clin Immunol. 2018 Apr;141(4):1220-1230
pubmed: 28734844
Nat Commun. 2014 Mar 18;5:3492
pubmed: 24637670
N Engl J Med. 2020 Jan 16;382(3):211-221
pubmed: 31851795
J Immunol. 2010 Jun 15;184(12):6929-37
pubmed: 20483774
Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9053-8
pubmed: 22611194
J Biomol Screen. 2005 Dec;10(8):823-31
pubmed: 16234346
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Am J Pathol. 2007 Nov;171(5):1407-18
pubmed: 17823281
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Int J Epidemiol. 2017 Dec 1;46(6):1734-1739
pubmed: 28398548
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10976-80
pubmed: 16043704
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Int J Biol Sci. 2015 Mar 20;11(4):482-93
pubmed: 25798067
FEBS Lett. 2012 Mar 23;586(6):705-10
pubmed: 22285490
Genomics. 2011 Dec;98(6):422-30
pubmed: 21903159
Acta Crystallogr D Struct Biol. 2016 Dec 1;72(Pt 12):1267-1280
pubmed: 27917827
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1398-405
pubmed: 27199449
Am J Hum Genet. 2015 Feb 5;96(2):275-82
pubmed: 25620204
Int J Cardiol. 2014 Oct 20;176(3):916-22
pubmed: 25171970
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
J Am Heart Assoc. 2018 Oct 16;7(20):e010025
pubmed: 30371289
Nat Rev Immunol. 2010 Dec;10(12):826-37
pubmed: 21088683
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):258-63
pubmed: 18172197
Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):33-9
pubmed: 18988894
J Am Chem Soc. 2011 Mar 23;133(11):3764-7
pubmed: 21355588
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
J Am Coll Cardiol. 2009 Feb 10;53(6):491-500
pubmed: 19195606
Science. 2008 Apr 18;320(5874):379-81
pubmed: 18420935
Circulation. 2011 Oct 18;124(16):1783-91
pubmed: 22007101
Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2480-8
pubmed: 18390820
PLoS Med. 2015 Mar 31;12(3):e1001779
pubmed: 25826379
Am J Physiol Cell Physiol. 2008 Jan;294(1):C29-35
pubmed: 17942642
Cell. 1985 Oct;42(3):791-8
pubmed: 3931919
Circ Cardiovasc Genet. 2009 Oct;2(5):489-98
pubmed: 20031625
PLoS One. 2015 Jun 10;10(6):e0126928
pubmed: 26061167
J Clin Invest. 2010 Dec;120(12):4251-72
pubmed: 21084753
Nat Commun. 2015 Sep 14;6:8111
pubmed: 26368830
Circulation. 2021 Jun 22;143(25):2418-2427
pubmed: 33913339
Heart. 2013 Mar;99(6):396-400
pubmed: 22942293
Nat Rev Immunol. 2015 Jul;15(7):429-40
pubmed: 26052098
J Tissue Eng Regen Med. 2018 Jan;12(1):e486-e494
pubmed: 27689683
JAMA Cardiol. 2018 Jan 1;3(1):18-23
pubmed: 29128868
J Biol Chem. 2006 May 12;281(19):13324-13332
pubmed: 16547006