# Mapping Drivers of Coronary Endothelial Activation and Endothelial‐to‐Mesenchymal Transition through Mimicking of Multimediator Inflammation in Kawasaki Disease Context

## TL;DR

This study explores how inflammation in Kawasaki disease affects coronary artery cells, identifying key proteins like IL-1β and LRG-1 that drive endothelial activation and transformation.

## Contribution

The study identifies IL-1 receptor type 1 inhibition as a key modulator of endothelial activation and EndMT in a multimediator inflammatory context of Kawasaki disease.

## Key findings

- KD serum and inflammatory matrix share 19 upregulated inflammatory proteins.
- IL-1R1 inhibition most effectively reduces endothelial activation in HCAECs.
- EndMT is partially reduced by IL-1R1 and tumor necrosis factor inhibition.

## Abstract

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.

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.

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.

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.