Mapping Drivers of Coronary Endothelial Activation and Endothelial‐to‐Mesenchymal Transition through Mimicking of Multimediator Inflammation in Kawasaki Disease Context
ACR Open Rheumatology, 2025
Buthe P., Limburg M., Fuehner S., Kuehn J., Jakob A., Koné‐Paut I., Tellier S., Belot A., Rossi‐Semerano L., Dusser‐Benesty P., Marie I., Merfort J., Masjosthusmann K., Hinze C., Wittkowski H., Foell D., Kessel C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Cell Culture Supernatant Serum |  Olink Target 96 |
Abstract
Objective
Kawasaki disease (KD) is an acute systemic vasculitis predominantly affecting coronary arteries of infants and children. We recently identified leucin‐rich α‐2‐glycoprotein 1 (LRG‐1) as known transforming growth factor β1 (TGFβ1) signal‐modulating molecule, orchestrating endothelial activation and cardiac remodeling, as associated with interleukin‐1β (IL‐1β) signaling in KD. In the present study, we aimed to assess the role for LRG‐1 as part of a multimediator inflammatory environment as a possible direct mediator of human coronary artery endothelial activation.
Methods
Human coronary artery endothelial cells (HCAECs) were treated with a blood inflammatory matrix, with or without targeted inhibition of several inflammatory mediators, including LRG‐1, and were analyzed for inflammatory activation or endothelial‐to‐mesenchymal transition (EndMT) on gene expression level. Proteomic profiling of the inflammatory matrix, treatment‐naïve KD (n = 11), or healthy control serum samples (n = 10) was performed by proximity extension assay (n = 184 markers) and Luminex.
Results
Proteomic analysis of KD serum samples and the inflammatory matrix revealed elevation of 37 versus 50 inflammatory proteins, respectively, with 19 significantly up‐regulated markers shared. The HCAEC culture with the inflammatory matrix resulted in inflammatory endothelial activation, which was most efficiently abrogated by IL‐1 receptor type 1 (IL‐1R1) inhibition compared to all other tested drugs. Whereas inflammatory endothelial activation can also link to TGFβ‐driven EndMT, which was supported by respective signatures in our KD serum proteomics, we observed that in vitro inflammatory matrix–induced EndMT was partly impaired by both IL‐1R1 and tumor necrosis factor inhibition compared to other tested drugs.
Conclusions
Collectively, our observations in the context of a multimediator inflammatory environment indicate a prominent role of a specific clinically relevant cytokine signaling axis in inflammatory coronary artery endothelial activation and EndMT in the context of KD.