Kawasaki disease OX40–OX40L axis acts as an upstream regulator of NFAT signaling pathway

Lv, Yu-Wen; Chen, Ye; Lv, Haitao; Li, Xuan; Tang, Yunjia; Qian, Weiguo; Xu, Qian; Qian, Guanghui; Ding, Yueyue

doi:10.1038/s41390-019-0312-0

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…We found the NFAT2 expression was significantly elevated in immune cells (PBMCs) from patients with KD, similar to a previous study ( 25 ). Previous research also reported that NFAT inhibitors, such as cyclosporine, can prevent progression of inflammation in the arterial wall by blocking cytotoxic CD8+T cells infiltration into the arterial wall ( 26 ).…”

Section: Discussionsupporting

confidence: 91%

The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease

et al. 2023

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AimsThe Ca+/NFAT (Nuclear factor of activated T cells) signaling pathway activation is implicated in the pathogenesis of Kawasaki disease (KD); however, we lack detailed information regarding the regulatory network involved in the human coronary endothelial cell dysfunction and cardiovascular lesion development. Herein, we aimed to use mouse and endothelial cell models of KD vasculitis in vivo and in vitro to characterize the regulatory network of NFAT pathway in KD.Methods and ResultsAmong the NFAT gene family, NFAT2 showed the strongest transcriptional activity in peripheral blood mononuclear cells (PBMCs) from patients with KD. Then, NFAT2 overexpression and knockdown experiments in Human coronary artery endothelial cells (HCAECs) indicated that NFAT2 overexpression disrupted endothelial cell homeostasis by regulation of adherens junctions, whereas its knockdown protected HCAECs from such dysfunction. Combined analysis using RNA-sequencing and transcription factor (TF) binding site analysis in the NFAT2 promoter region predicted regulation by Forkhead box O4 (FOXO4). Western blotting, chromatin immunoprecipitation, and luciferase assays validated that FOXO4 binds to the promoter and transcriptionally represses NFAT2. Moreover, Foxo4 knockout increased the extent of inflamed vascular tissues in a mouse model of KD vasculitis. Functional experiments showed that inhibition NFAT2 relieved Foxo4 knockout exaggerated vasculitis in vivo.ConclusionsOur findings revealed the FOXO4/NFAT2 axis as a vital pathway in the progression of KD that is associated with endothelial cell homeostasis and cardiovascular inflammation development.

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Section: Discussionsupporting

confidence: 91%

The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease

et al. 2023

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“…MDM2 inhibits T-cell activation by targeting the ubiquitination-mediated degradation of nuclear transcription factor 1 (NFAT1) ( 7 ). We found that the NFAT signaling pathway is involved in immune damage in patients with KD in another study ( 10 ). Therefore, we hypothesized that the ubiquitination of proteins associated with MDM2 plays a crucial role in KD.…”

Section: Introductionmentioning

confidence: 66%

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development

Xu,

Qian,

Zhu

et al. 2024

Transl Pediatr

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Background Kawasaki disease (KD) often complicates coronary artery lesions (CALs). Despite the established significance of STAT3 signaling during the acute phase of KD and signal transducer and activator of transcription 3 (STAT3) signaling being closely related to CALs, it remains unknown whether and how STAT3 was regulated by ubiquitination during KD pathogenesis. Methods Bioinformatics and immunoprecipitation assays were conducted, and an E3 ligase, murine double minute 2 (MDM2) was identified as the ubiquitin ligase of STAT3. The blood samples from KD patients before and after intravenous immunoglobulin (IVIG) treatment were utilized to analyze the expression level of MDM2. Human coronary artery endothelial cells (HCAECs) and a mouse model were used to study the mechanisms of MDM2-STAT3 signaling during KD pathogenesis. Results The MDM2 expression level decreased while the STAT3 level and vascular endothelial growth factor A (VEGFA) level increased in KD patients with CALs and the KD mouse model. Mechanistically, MDM2 colocalized with STAT3 in HCAECs and the coronary vessels of the KD mouse model. Knocking down MDM2 caused an increased level of STAT3 protein in HCAECs, whereas MDM2 overexpression upregulated the ubiquitination level of STAT3 protein, hence leading to significantly decreased turnover of STAT3 and VEGFA. Conclusions MDM2 functions as a negative regulator of STAT3 signaling by promoting its ubiquitination during KD pathogenesis, thus providing a potential intervention target for KD therapy.

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“…We suspect that coordination of, and regulation by, canonical and non-canonical NF-kB pathways may also be related to local increased expression of TNFRSF4, MT2A, and PIM3 that we observed in our analysis [45]. Indeed, TNFRSF4, or OX40, encodes a ligand receptor of the TNF superfamily that is typically expressed by T-cells 24-72 h after activation [46][47][48][49][50][51][52][53]. This receptor has been shown to activate NF-kB via its interaction with adaptor proteins TRAF2 and TRAF5 (non-canonical).…”

Section: Discussionmentioning

confidence: 94%

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Tutino

Ishii

et al. 2021

Diagnostics

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The rupture of an intracranial aneurysm (IA) causes devastating hemorrhagic strokes. Yet, most IAs remain asymptomatic and undetected until they rupture. In the search for circulating biomarkers of unruptured IAs, we previously performed transcriptome profiling on whole blood and identified an IA-associated panel of 18 genes. In this study, we seek to determine if these genes are also differentially expressed within the IA lumen, which could provide a mechanistic link between the disease and the observed circulating gene expression patterns. To this end, we collected blood from the lumen of 37 IAs and their proximal parent vessels in 31 patients. The expression levels of 18 genes in the lumen and proximal vessel were then measured by quantitative polymerase chain reaction. This analysis revealed that the expression of 6/18 genes (CBWD6, MT2A, MZT2B, PIM3, SLC37A3, and TNFRSF4) was significantly higher in intraluminal blood, while the expression of 3/18 genes (ST6GALNAC1, TCN2, and UFSP1) was significantly lower. There was a significant, positive correlation between intraluminal and proximal expression of CXCL10, MT2A, and MZT2B, suggesting local increases of these genes is reflected in the periphery. Expression of ST6GALNAC1 and TIFAB was significantly positively correlated with IA size, while expression of CCDC85B was significantly positively correlated with IA enhancement on post-contrast MRI, a metric of IA instability and risk. In conclusion, intraluminal expression differences in half of the IA-associated genes observed in this study provide evidence for IA tissue-mediated transcriptional changes in whole blood. Additionally, some genes may be informative in assessing IA risk, as their intraluminal expression was correlated to IA size and aneurysmal wall enhancement.

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Kawasaki disease OX40–OX40L axis acts as an upstream regulator of NFAT signaling pathway

Cited by 5 publications

References 35 publications

The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease

The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

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