Epigenetic Regulation of Macrophage Marker Expression Profiles in Kawasaki Disease

Abstract

Kawasaki disease (KD) is a common systemic vasculitides in children younger than 5 years of age. Activated macrophages are key drivers of vascular inflammation in KD. The aim of this study was to examine differences in M1 and M2 macrophage marker expression in patients with KD. Blood samples were obtained from 18 healthy controls and 18 patients with KD at 24 h prior and 21 days after to intravenous immunoglobulin therapy. GeneChip Human Transcriptome Array 2.0 and Illumina HumanMethylation450 BeadChip were used to examined the mRNA expression and corresponding CpG site methylation ratios of 10 M1 surface markers and 15 M2 surface markers. Of the markers examined 2 M1 markers (TLR2, IL2RA) and 8 M2 markers (ARG1, CCR2, TLR1, TLR8, TLR5, MS4A6A, CD36, and MS4A4A) showed increased mRNA expression in the acute phase of KD which decreased after IVIG therapy (P < 0.05). Corresponding CpG sites in the promoter regions these markers were hypomethylated in the acute phase of KD and significantly increased after IVIG therapy. In conclusion, both M1 and M2 markers showed increased mRNA expression in the acute phase of KD. CpG site methylation may be one of the mechanisms governing macrophage polarization in KD.

Kawasaki Disease and Allergic Diseases

“…The lungs' classically activated macrophages (M1) expressing proinflammatory cytokines and alternatively activated macrophages (M2) expressing Th2 cytokines both participate in the pathogenesis of asthma (59). One recent study suggested that M1 and M2 cells are distinct cell subtypes that play separate roles in the immunopathogenesis of KD and also showed M2 to be predominant (Figure 2) (60).…”

Toll-like receptor 4 methylation grade is linked to depressive symptom severity

“…We used two TLR4 RNA probes in the Danish twin study and both probes were significantly inversely correlated to TLR4 methylation. In a recent report by Guo et al, patients with Kawasaki disease had decreased methylation in leukocytes of cg05429895 (and two other TLR4 CpGs) and higher mRNA TLR4 levels [67], indicating that an increase in methylation at this particular site likely contributes to decreased RNA expression levels. Elevated TLR4 mRNA has been described before in blood cells from depressed patients [15,26,].…”

Epigenetics in Kawasaki Disease

“…Recently, transcriptomic profiling using GeneChip array in patients with acute phase of KD has showed elevated expression of TLR2 and IL2RA (M1 macrophage) in addition to markers associated with M2 macrophage (e.g., MS4A4A, MS4A6A, TLR1, TLR8, TLR5, CD36, CCR2, and ARG1). Authors have also noted hypomethylation of the promoter region of respective genes (17). IVIg treatment given to these patients has further enhanced the expression pattern of these genes by enriching the hypomethylation status.…”

“…Epigenetics is widely explored in most of complex heterogenic diseases like KD where contribution of both genetic and environmental factors is equally shared (14)(15)(16)(17). Genetic predisposition of complex disease phenotypes has been associated with substantial contribution of dysregulated epigenetic factors.…”

“…Complex genetic architecture of KD suggests contribution of several innate and adaptive immune responses, extracellular matrix (ECM) components and proteins regulating its remodelling, and angiogenic proteins (14)(15)(16)(17). Apart from widely explored genetic network in KD, a well-defined biomarker for diagnosis and prognostication has not yet been established.…”