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

Can Gollmann-Tepeköylü, Michael Graber, Jakob Hirsch, Sophia Mair, Andreas Naschberger, Leo Pölzl, Leo Pölzl, Felix Nägele, Elke Kirchmair, Gerald Degenhart, Egon Demetz, Richard Hilbe, Hao-Yu Chen, James C Engert, Anna Böhm, Nadja Franz, Daniela Lobenwein, Daniela Lener, Christiane Fuchs, Anna WeihsSonja Töchterle, Georg F Vogel, Victor Schweiger, Jonas Eder, Peter Pietschmann, Markus Seifert, Florian Kronenberg, Stefan Coassin, Michael Blumer, Hubert Hackl, Dirk Meyer, Gudrun Feuchtner, Rudolf Kirchmair, Jakob Troppmair, Markus Krane, Günther Weiss, Sotirios Tsimikas, George Thanassoulis, Michael Grimm, Bernhard Rupp, Lukas A Huber, Shen-Ying Zhang, Jean-Laurent Casanova, Ivan Tancevski, Johannes Holfeld

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 byglycan (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.
Original languageEnglish (US)
JournalCirculation
DOIs
StatePublished - Apr 4 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-04-11
Acknowledgements: This work was supported by grants from the “Gesellschaft zur Förderung der Herz-Kreislaufforschung in Tirol “(to Dr Gollmann-Tepeköylü), Bayer Grants4Tar-gets (No.2014-08-1162), the Austrian Science Fund (FWF) to Drs Gollmann-Tepeköylü, Hirsch, and Tancevski (P 32821), “Medizinischer Forschungsfond Tirol” (No. 257) to Drs Gollmann-Tepeköylü and Hirsch. It was also supported in part by the Austrian Science Fund (FWF) under project P28395-B26 to Dr Rupp, project I-3321 grants to Dr Weiss, the City of Vienna Competence Team Signal Tissue (MA23#18-08), and the City of Vienna Competence Team Aging Tissue (MA23#29-07). This study is supported by VASCage–Research Centre on Vascular Ageing and Stroke. VASCage is a COMET Centre within the Competence Centers for Excellent Technologies (COMET) program and funded by the Federal Ministry for Climate Action, Environment, Energy, Mobility, Innovation and Technology, the Federal Ministry of Labour and Economy, and the federal states of Tyrol, Salzburg, and Vienna. This work was partially supported by funding to Dr Thanassoulis from the Canadian Institutes of Health Research, National Institutes of Health/National Heart, Lung, and Blood Insti-tute (HL128550), the Heart and Stroke Foundation of Canada, and the “Fonds de Recherche Québec–Santé.”

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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