变异rs13045在川崎病中通过MAPK-ERK1/2通路降低EIF2AK3表达并抑制促炎细胞因子分泌。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-09-03 DOI:10.1016/j.bbadis.2025.168032

Wan Yang , Wenli Guo , Zhouping Wang , Linjie Jiang , Xilian Luo , Kaining Chen , Xiaofang Liu , Can An , Lei Pi , Yufen Xu , Lanyan Fu , Huazhong Zhou , Xiaoqiong Gu , Di Che , Jianrui Wei , Hongyan Yu

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引用次数: 0

摘要

目的：川崎病（KD）是一种急性全身性血管炎，是发达国家儿童获得性心脏病的主要原因。本研究旨在探索EIF2AK3在kd相关血管炎中的作用及其潜在机制，从而为治疗提供新的视角。方法：采用TaqMan®对910例KD患者和848例对照者的DNA进行rs13045基因分型，分析其与KD易感性的关系。同时，使用qRT-PCR、Western blot和免疫荧光技术评估KD炎症条件下EIF2AK3的表达。检测EIF2AK3敲低或过表达后的促炎细胞因子水平，并对下游信号通路进行RNA测序。在体内实验中，我们建立了干酪乳杆菌细胞壁提取物（Lactobacillus casei cell wall extract， LCWE）诱导的EIF2AK3基因敲低的KD小鼠模型。ELISA和HE染色检测EIF2AK3敲低组与对照组的血管炎程度。结果：EIF2AK3/rs13045多态性与KD易感性相关，其中rs13045 C等位基因下调EIF2AK3。在KD炎症条件下，EIF2AK3表达显著增加。EIF2AK3敲低或药理抑制（GSK2606414）可降低促炎细胞因子（IL-1β/IL-6/IL-8/TNF-α）的表达，而过表达EIF2AK3可升高促炎细胞因子的表达。在机制上，EIF2AK3通过激活MAPK-ERK1/2通路促进促炎细胞因子的表达。此外，EIF2AK3下调抑制了内皮到间质转化（EndoMT），从而损害了huvec的迁移。这些发现在KD小鼠模型中也得到了概括。结论：EIF2AK3/rs13045是中国南方人群KD易感位点。我们的研究结果表明，EIF2AK3上调促炎细胞因子，从而通过MAPK-ERK1/2途径促进kd相关血管炎。这一发现表明EIF2AK3是治疗KD的潜在治疗靶点。

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Variant rs13045 reduces EIF2AK3 expression and inhibits pro-inflammatory cytokine secretion via the MAPK-ERK1/2 pathway in Kawasaki disease

Purpose

Kawasaki disease (KD) is an acute systemic vasculitis and a leading cause of acquired heart disease in children in developed countries. This study endeavors to explore the role and underlying mechanisms of EIF2AK3 in KD-related vasculitis, thereby offering novel therapeutic perspectives.

Methods

DNA from 910 KD patients and 848 controls were genotyped for rs13045 using TaqMan® to analyze the association with KD susceptibility. Concurrently, EIF2AK3 expression under KD inflammatory conditions was assessed using qRT-PCR, Western blot, and immunofluorescence. Pro-inflammatory cytokine levels were measured following EIF2AK3 knockdown or overexpression, and RNA sequencing was explored the downstream signaling pathways. For in vivo experiment, a Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model with Eif2ak3 knockdown was established. ELISA and HE staining were used to investigate the degree of vasculitis between Eif2ak3 knockdown and control groups.

Results

The EIF2AK3/rs13045 polymorphism was associated with KD susceptibility, with the rs13045 C allele downregulating EIF2AK3. EIF2AK3 expression was increased significantly during KD inflammatory conditions. EIF2AK3 knockdown or pharmacological inhibition (GSK2606414) reduced pro-inflammatory cytokines (IL-1β/IL-6/IL-8/TNF-α) expression, while overexpression of EIF2AK3 elevated them. Mechanistically, EIF2AK3 promoted pro-inflammatory cytokines expression through activation of the MAPK-ERK1/2 pathway. Furthermore, EIF2AK3 downregulation inhibited the endothelial-to-mesenchymal transition (EndoMT), thereby impairing HUVECs migration. These findings were also recapitulated in the KD mouse model.

Conclusion

EIF2AK3/rs13045 is a novel susceptibility locus for KD in the southern Chinese population. Our findings reveal that EIF2AK3 upregulates pro-inflammatory cytokines, thereby promoting KD-associated vasculitis via the MAPK-ERK1/2 pathway. This discovery suggests EIF2AK3 as a potential therapeutic target for the management of KD.

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.