IL-17-associated Pro-inflammatory Programs in Aortic Valve Interstitial Cell Osteogenic Differentiation: JUN as a Candidate Regulator.

Authors

Yining Dai, Siyu Kong, Yupeng Yang, Yeshen Zhang, Yu He, Pengda He, Haobin Liu, Ning Tan, Pengcheng He, Ling Xue, Zhenyang Fu, Yuanhui Liu

Published in

Inflammation. Jul 21, 2026. Epub Jul 21, 2026.

Abstract

Calcific aortic valve disease (CAVD) involves fibro-calcific remodeling, in which osteogenic differentiation of valvular interstitial cells (VICs) is a key process. Although inflammation is implicated, uncertainties persist regarding how defined pro-inflammatory pathways are transcriptionally coupled to the VIC osteogenic program at the cell-intrinsic level. We implemented an interleukin-17 (IL-17) pathway-guided transcriptomic strategy in a pure human VIC osteogenic differentiation model. RNA sequencing identified osteogenesis-associated differentially expressed genes and IL-17-related inflammatory signatures. Functional enrichment and multilayer network analyses were applied to prioritize candidate regulatory nodes, followed by in vitro validation. An IL-17-associated transcriptional program was activated during VIC osteogenic differentiation and was enriched for stress-activated and MAPK-related inflammatory pathways. Network-based analyses consistently identified the AP-1 transcription factor JUN as a central regulatory node within this IL-17-linked signature. Experimentally, JUN expression increased during VIC osteogenic differentiation, and JUN silencing attenuated calcification. IL-17 A rapidly increased the p-c-JUN/JUN ratio, and prolonged treatment upregulated JUN and IL-17RA in a concentration-dependent manner. Exogenous IL-17 A stimulation enhanced calcification-related phenotypes in VICs, which were partially reversed by JUN knockdown. In a chronic kidney disease-induced mouse CAVD model, JNK inhibition with SP600125 reduced valve calcification and leaflet thickness. IL-17-associated inflammatory signaling is engaged during VIC osteogenic differentiation and may promote calcification, partially through a JUN-dependent mechanism. These findings provide insight into how inflammatory programs interface with osteogenic transcription and offer a framework for dissecting inflammation-driven calcification in CAVD.

PMID:
42479100
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.

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