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