Macrophage-derived IL-18 aggravates fibrocalcific remodeling of valvular interstitial cells
Z Zhang, S Shu, Q Yang, X Wang, H Gao, H Shi, Z Luo, J Song, X WangAbstract
Background
Aortic valve stenosis (AVS) is the most common valvular heart disease, characterized by a chronic inflammatory state and osteogenic differentiation of valvular interstitial cells (VIC). The cytokine IL-18 plays an important role in various inflammatory diseases, but its role in AVS is not yet clear.
Methods
The UK Biobank database was used to analyze the association between plasma IL-18 levels and the risks of AVS . Case-control analyses revealed elevated IL-18 expression in patients with AVS. Additionally, using single-cell RNA sequencing, we identified the cellular sources of IL-18 and the phenotypic states of VIC. Cellular and animal models were further employed to investigate the functional role and underlying mechanisms of IL-18 in AVS.
Results
Data from the UK Biobank revealed that elevated baseline plasma IL-18 levels were significantly associated with an increased risk of aortic valve calcification events and subsequent aortic valve replacement surgery. Multivariable Cox proportional hazards analysis demonstrated that this association remained independent after adjustment for traditional cardiovascular risk factors. ScRNA-seq of human aortic valve tissue identified macrophages as the primary source of IL-18, and the expression level of IL18 in macrophages from AVS was higher than that in macrophages from the control group.In vitro, stimulation of primary VIC with recombinant IL-18 protein directly promoted calcification in a dose-dependent manner. In DWI model mice and AopE-/- model mice, recombinant IL-18 was shown to exacerbate aortic valve flow velocity, increase leaflet thickness, and promote fibro-calcific remodeling. Furthermore, a macrophage-VIC co-culture system confirmed that macrophage-derived IL-18 is a key factor in VIC fibro-calcific remodeling.
Conclusion
These findings suggest that macrophage-derived IL-18 promotes AVS progression by directly inducing osteogenic differentiation of valvular interstitial cells, highlighting IL-18 as a potential therapeutic target for this disease.graphical abstract