Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

Autor:	Gollmann-Tepeköylü C; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Graber M; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Hirsch J; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Mair S; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Naschberger A; Institute of Genetic Epidemiology, Department of Genetics and Pharmacology (A.N., F.K., S.C., B.R.), Medical University of Innsbruck, Austria.; Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal4 Saudi Arabia (A.N.)., Pölzl L; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Nägele F; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Kirchmair E; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria.; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Degenhart G; Department of Radiology, Core Facility for Micro-CT (G.D., G.F.), Medical University of Innsbruck, Austria., Demetz E; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Hilbe R; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Chen HY; Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, Quebec, Canada (J.C.E., H.-Y.C., G.T.)., Engert JC; Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, Quebec, Canada (J.C.E., H.-Y.C., G.T.)., Böhm A; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Franz N; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Lobenwein D; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Lener D; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Fuchs C; Department Life Science Engineering (C.F., A.W.), University of Applied Sciences Technikum Wien, Vienna, Austria., Weihs A; Department Life Science Engineering (C.F., A.W.), University of Applied Sciences Technikum Wien, Vienna, Austria., Töchterle S; Institute of Molecular Biology/CMBI (S.T., D.M.), Medical University of Innsbruck, Austria., Vogel GF, Schweiger V; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Eder J; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Pietschmann P; Division of Cellular and Molecular Pathophysiology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria (P.P.)., Seifert M; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Kronenberg F; Institute of Genetic Epidemiology, Department of Genetics and Pharmacology (A.N., F.K., S.C., B.R.), Medical University of Innsbruck, Austria., Coassin S; Institute of Genetic Epidemiology, Department of Genetics and Pharmacology (A.N., F.K., S.C., B.R.), Medical University of Innsbruck, Austria., Blumer M; Institute of Clinical and Functional Anatomy, Innsbruck Medical University, Austria (M.B.)., Hackl H; Institute of Bioinformatics (H.H.), Medical University of Innsbruck, Austria., Meyer D; Institute of Molecular Biology/CMBI (S.T., D.M.), Medical University of Innsbruck, Austria., Feuchtner G; Department of Radiology, Core Facility for Micro-CT (G.D., G.F.), Medical University of Innsbruck, Austria., Kirchmair R; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Troppmair J; Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery (J.T.), Medical University of Innsbruck, Austria., Krane M; Department of Cardiovascular Surgery, German Heart Center Munich at the Technical University Munich, Germany (M.K.)., Weiss G; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Tsimikas S; Division of Cardiovascular Diseases, University of California, San Diego, La Jolla (S.T.)., Thanassoulis G; Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, Quebec, Canada (J.C.E., H.-Y.C., G.T.)., Grimm M; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria., Rupp B; Institute of Genetic Epidemiology, Department of Genetics and Pharmacology (A.N., F.K., S.C., B.R.), Medical University of Innsbruck, Austria., Huber LA; Institute of Cell Biology (L.A.H.), Medical University of Innsbruck, Austria.; Austrian Drug Screening Institute, ADSI, Innsbruck (L.A.H.)., Zhang SY; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY (S.-Y.Z., J.-L.C.).; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France (S.-Y.Z., J.-L.C.).; University of Paris, Imagine Institute, France (S.-Y.Z., J.-L.C.)., Casanova JL; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY (S.-Y.Z., J.-L.C.).; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France (S.-Y.Z., J.-L.C.).; University of Paris, Imagine Institute, France (S.-Y.Z., J.-L.C.).; Howard Hughes Medical Institute, New York, NY (J.-L.C.)., Tancevski I; Department of Internal Medicine III (E.D., R.H., A.B., D. Lener, M.S., R.K., G.W., I.T.), Medical University of Innsbruck, Austria., Holfeld J; Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2023 May 16; Vol. 147 (20), pp. 1518-1533. Date of Electronic Publication: 2023 Apr 04.
DOI:	10.1161/CIRCULATIONAHA.122.063481
Abstrakt:	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 ( Bgn ), Tlr3 , and IFN-α/β receptor alpha chain ( Ifnar1 )-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. 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 Bgn -/- , Tlr3 -/- , and Ifnar1 -/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. 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. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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