MicroRNA-145-5p and microRNA-320a encapsulated in endothelial microparticles contribute to the progression of vasculitis in acute Kawasaki Disease

Hideyuki Nakaoka,Koshi Kinoshita,Seiji Yamamoto,Keiichi Hirono,Mako Okabe,Keijiro Ibuki,Ichiro Takasaki,Yuichi Adachi,Fukiko Ichida,Kei Takahashi,Nariaki Miyao,Wang Ce,Kazuyoshi Saito,Naonori Nishida,Sayaka Ozawa,Asami Takasaki

doi:10.1038/s41598-018-19310-4

Hideyuki Nakaoka, Koshi Kinoshita + Show 14 more

Open Access

https://doi.org/10.1038/s41598-018-19310-4

Copy DOI

Abstract

Kawasaki Disease (KD) is an acute inflammatory disease that takes the form of systemic vasculitis. Endothelial microparticles (EMPs) have been recognized as an important transcellular delivery system. We hypothesized whether EMPs are involved in vasculitis in acute KD. Fifty patients with acute KD were enrolled, divided into two subgroups: those with coronary artery lesions (CAL) (n = 5) and those without CAL (NCAL) (n = 45). EMPs were measured using flow cytometry, and microRNA (miR) expression profiling was performed by microRNA array. The percentage of EMPs in acute KD was significantly higher than in controls (P < 0.0001). EMPs in patients with CAL rapidly increased after the initial treatment, and was significantly higher than those in NCAL (P < 0.001). In patients with CAL, we identified 2 specific miRs encapsulated in EMPs, hsa-miR-145-5p and hsa-miR-320a, which are predicted to affect monocyte function using in silico analysis, and were demonstrated to upregulate inflammatory cytokine mRNAs in THP-1 monocytes. In situ hybridization confirmed that hsa-miR-145-5p was preferentially expressed in CAL. EMPs may serve as a sensitive marker for the severity of vasculitis in acute KD. Moreover, these 2 specific miRs encapsulated in EMPs might be involved in inflammatory cytokine regulation and the pathogenesis of vasculitis in acute KD.

Highlights

Kawasaki Disease (KD) is typically an acute inflammatory syndrome that takes the form of systemic vasculitis[1]
All of the patients with coronary artery lesions (CAL) were refractory to intravenous immunoglobulin (IVIG) treatment
To elucidate which molecules are associated with adverse outcomes during acute KD, we focused on the role of miRs as the bioactive molecules[7], and in particular those present in endothelial microparticles (EMPs), which we have shown previously to be involved in the pathogenesis of KD3

Summary

Introduction

Kawasaki Disease (KD) is typically an acute inflammatory syndrome that takes the form of systemic vasculitis[1]. MiRs are non-coding, single stranded RNAs, 18–24-nucleotide in length, that exert the ability to negatively regulate the expression of target genes, and are involved in several cellular processes including cell proliferation, apoptosis, migration, invasion, and stress response[11,12,13]. EMPs can transduce cellular signals from the endothelial cells to various target cells by encapsulated small molecules[7], or alternatively through secretion of soluble mediators and effectors[14]. There have been few studies investigating the role of miRs that can be encapsulated in EMPs, in patients with acute KD. It is still unknown whether these miRs can communicate with various target cells, and regulate inflammatory cytokines. Our findings suggest that identified miRs may be encapsulated in EMPs and can modulate cytokine expression levels in recipient cells

Methods

Results

Discussion

Conclusion