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METTL3-mediated m6A Methylation Modification Promotes the Endothelial Cell Pyroptosis in Kawasaki Disease
Bingbing Qiu1,2, Chengyi Wang3, Changdi Chen2
1College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, No.966, Hengyu Road, Gushan Town, Jin'an District, Fuzhou City, Fujian Province, 350001, China.
Insights
Methyltransferase-like protein 3 (METTL3) promotes endothelial cell pyroptosis in Kawasaki disease (KD) through N6-methyladenosine (m6A) modification, offering insights into KD pathogenesis and potential therapeutic targets.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Kawasaki disease (KD) is an acute febrile illness involving systemic vasculitis.
- The role of N6-methyladenosine (m6A) modification in KD pathogenesis is currently unknown.
- Understanding m6A's role could reveal new therapeutic strategies for KD.
Purpose of the Study:
- To investigate the influence of m6A modification in Kawasaki disease.
- To elucidate the underlying molecular mechanisms of m6A in KD.
- To explore METTL3's specific role in KD-induced endothelial cell pyroptosis.
Main Methods:
- Expression analysis of m6A-related enzymes using RT-qPCR.
- Assessment of pyroptosis markers (LDH, IL-1β, IL-18) and cell death.
- Western blot for pyroptosis proteins, RIP and dual-luciferase assays for METTL3-NLRC4 interaction.
- Induction of a KD mouse model and subsequent analysis.
Main Results:
- Elevated METTL3 expression was observed in KD patient serum.
- KD serum induced pyroptosis in human umbilical vein endothelial cells (HUVECs).
- METTL3 stabilized NLRC4 mRNA via m6A methylation, promoting pyroptosis; METTL3 inhibition reduced disease severity in a mouse model.
Conclusions:
- METTL3-mediated m6A modification promotes endothelial cell pyroptosis in KD.
- This mechanism highlights a novel pathway in KD pathogenesis.
- Targeting METTL3 may offer a potential therapeutic approach for Kawasaki disease.
Abstract:
Kawasaki disease (KD) is classified as an acute febrile illness characterized primarily by systemic vasculitis. While the involvement of N6-methyladenosine (m6A) modification in various cardiovascular conditions has been established, its specific role in KD remains unexplored. This study aims to investigate the potential influence of m6A modification in KD and to elucidate the mechanisms involved. Clinically, 18 KD patients and 15 healthy volunteers were recruited. Reverse transcription-quantitative polymerase chain reactio (RT-qPCR) was performed to assess the expression of m6A-related enzymes. Lactate dehydrogenase (LDH) release, interleukin (IL)-1β and IL-18 concentrations were analyzed by commercial kits. Hoechst 33,342/PI staining was performed for cell death detection. Pyroptosis-related protein levels were detected by Western blot. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were performed to assess the interaction between methyltransferase-like protein 3 (METTL3) and Nod-like receptor (NLR) family CARD domain-containing protein 4 (NLRC4). Finally, a KD mouse model was induced by Candida albicans cell wall extracts. Results showed that serum from KD patients exhibited higher METTL3 expression. Additionally, KD serum-treated THP1 cells induced pyroptosis of human umbilical vein endothelial cells (HUVECs). Mechanistically, METTL3 promoted the stability of NLRC4 mRNA via m6A methylation. Furthermore, NLRC4 overexpression promoted pyroptosis in KD-treated HUVECs. Finally, METTL3 inhibition attenuated coronary arteritis and pyroptosis in a KD mouse model. In summary, this study concluded that METTL3-mediated m6A methylation modification promoted the endothelial cell pyroptosis in KD, which might provide a reference for the pathogenesis of KD.
