Toll-like receptor 3 mediates calcific aortic valve disease via a conserved mechanism of calcification

The molecular mechanisms underlying valvular immunaging are not well understood. Toll-like receptors (TLRs) are evolutionary conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Here, we identify TLR3 as a central molecular regulator of calcification in cells exposed to mechanical strain. TLR3 is responsible for the phenotypic switch of valvular interstitial cells (VICs) to bone-forming cells in aortic valves and drives bone formation in vertebrates. Tlr3-/- mice exhibit an osteoporotic phenotype and are protected from CAVD. Moreover, we uncover biglycan (BGN), an extracellular matrix protein released upon mechanical tissue damage, as the first known endogenous TLR3-ligand and provide compelling evidence for receptor-ligand interaction. Our results reveal novel insights in the pathogenesis of CAVD and uncover TLR3 as a potential therapeutic target to prevent cardiovascular calcification and death. Overall design: Gene expression profiling of human valvular interstitial cells (untreated and treated with 20 µg/mL Poly (I:C) for 72h), human osteoblasts, human dermal fibroblasts (untreated and treated with 20 µg/mL Poly (I:C) for 72h)