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

Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

Mucocutaneous Lymph Node Syndrome*/metabolism ; Mucocutaneous Lymph Node Syndrome*/pathology ; Mucocutaneous Lymph Node Syndrome*/genetics ; DNA, Mitochondrial*/genetics ; DNA, Mitochondrial*/metabolism ; Nucleotidyltransferases*/metabolism ; Nucleotidyltransferases*/genetics ; Membrane Proteins*/metabolism ; Membrane Proteins*/genetics ; Inflammation*/pathology ; Inflammation*/metabolism ; Inflammation*/genetics ; Mitochondrial Permeability Transition Pore*/metabolism ; Signal Transduction*; Humans ; Animals ; Male ; Mice ; Human Umbilical Vein Endothelial Cells/metabolism ; Female ; Acute Disease ; Mice, Inbred C57BL ; Child, Preschool

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.
(© 2024. The Author(s).)

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SJCX23_1802 Graduate Practice Innovation Program of Jiangsu Province; SYH-32034-0082 Jiangsu Provincial Medical Association; 82270528 National Natural Science Foundation of China; ZDA2020010 Jiangsu Provincial Commission of Health and Family Planning; MS22022116 People's Livelihood Science and Technology Projetct of Nantong Science and Technology Bureau; F202154 Maternal and Child Health Project of Jiangsu Provincial Health Commission; LCYJ-A06 Multi-centre Clinical Collaborative Research Project at Affiliated Hospital of Nantong University; NTCXTD43 Nantong Municipal Health Commission 14th Five-Year Plan Innovation Team

Keywords: Kawasaki disease; cGAS-STING pathway; mPTP; mtDNA

0 (DNA, Mitochondrial)
EC 2.7.7.- (Nucleotidyltransferases)
0 (Membrane Proteins)
0 (Mitochondrial Permeability Transition Pore)
0 (STING1 protein, human)
EC 2.7.7.- (cGAS protein, human)

Date Created: 20240613 Date Completed: 20240614 Latest Revision: 20240626

20240626

PMC11177463

10.1186/s12964-024-01677-9

38872145