线粒体 DNA 通过线粒体通透性转换孔释放，激活 cGAS-STING 通路，加重急性川崎病的炎症反应。

Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease.

机构信息

Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.

Research Institute of Comparative Medicine, Nantong University, Nantong, 226001, Jiangsu Province, China.

出版信息

Cell Commun Signal. 2024 Jun 13;22(1):328. doi: 10.1186/s12964-024-01677-9.

DOI:10.1186/s12964-024-01677-9

PMID:38872145

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11177463/

Abstract

BACKGROUND

Kawasaki disease (KD) is an immune vasculitis of unknown origin, characterized by transient inflammation. The activation of the cGAS-STING pathway, triggered by mitochondrial DNA (mtDNA) release, has been implicated in the onset of KD. However, its specific role in the progression of inflammation during KD's acute phase remains unclear.

METHODS

We measured mtDNA and 2'3'-cGAMP expression in KD patient serum using RT-qPCR and ELISA. A murine model of KD was induced by injecting Lactobacillus casei cell wall extract (LCWE), after which cGAS-STING pathway activation and inflammatory markers were assessed via immunohistochemistry, western blot, and RT-qPCR. Human umbilical vein endothelial cells (HUVECs) were treated with KD serum and modulators of the cGAS-STING pathway for comparative analysis. Mitochondrial function was evaluated using Mitosox staining, mPTP opening was quantified by fluorescence microscopy, and mitochondrial membrane potential (MMP) was determined with JC-1 staining.

RESULTS

KD patient serum exhibited increased mtDNA and 2'3'-cGAMP expression, with elevated levels of pathway-related proteins and inflammatory markers observed in both in vivo and in vitro models. TEM confirmed mitochondrial damage, and further studies demonstrated that inhibition of mPTP opening reduced mtDNA release, abrogated cGAS-STING pathway activation, and mitigated inflammation.

CONCLUSION

These findings indicate that mtDNA released through the mPTP is a critical activator of the cGAS-STING pathway, contributing significantly to KD-associated inflammation. Targeting mtDNA release or the cGAS-STING pathway may offer novel therapeutic approaches for KD management.

摘要

背景

川崎病（KD）是一种病因不明的免疫性血管炎，其特征为短暂性炎症。线粒体 DNA（mtDNA）释放触发的 cGAS-STING 通路的激活已被认为与 KD 的发病有关。然而，其在 KD 急性期炎症进展中的具体作用尚不清楚。

方法

我们使用 RT-qPCR 和 ELISA 测量了 KD 患者血清中的 mtDNA 和 2'3'-cGAMP 表达。通过注射干酪乳杆菌细胞壁提取物（LCWE）诱导 KD 小鼠模型，通过免疫组织化学、western blot 和 RT-qPCR 评估 cGAS-STING 通路的激活和炎症标志物。用 KD 血清和 cGAS-STING 通路调节剂处理人脐静脉内皮细胞（HUVEC）进行比较分析。用 Mitosox 染色评估线粒体功能，通过荧光显微镜定量 mPTP 开放，用 JC-1 染色测定线粒体膜电位（MMP）。