학술논문
Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease.
Document Type
Academic Journal
Author
Tumburu L; Sickle Cell Branch.; Ghosh-Choudhary S; Sickle Cell Branch.; Seifuddin FT; Bioinformatics and Computational Biology Core.; Barbu EA; Sickle Cell Branch.; Yang S; Sickle Cell Branch.; Ahmad MM; Sickle Cell Branch.; Wilkins LHW; Sickle Cell Branch.; Tunc I; Bioinformatics and Computational Biology Core.; Sivakumar I; Sickle Cell Branch.; Nichols JS; Sickle Cell Branch.; Dagur PK; Flow Cytometry Core, and.; Yang S; Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.; Almeida LEF; Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD; and.; Quezado ZMN; Sickle Cell Branch.; Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD; and.; Combs CA; Light Microscopy Core.; Lindberg E; Electron Microscopy Core Facility, and.; Bleck CKE; Electron Microscopy Core Facility, and.; Zhu J; Single Cell Genomics Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.; Shet AS; Sickle Cell Branch.; Chung JH; Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.; Pirooznia M; Bioinformatics and Computational Biology Core.; Thein SL; Sickle Cell Branch.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
Subject
Language
English
Abstract
The pathophysiology of sickle cell disease (SCD) is driven by chronic inflammation fueled by damage associated molecular patterns (DAMPs). We show that elevated cell-free DNA (cfDNA) in patients with SCD is not just a prognostic biomarker, it also contributes to the pathological inflammation. Within the elevated cfDNA, patients with SCD had a significantly higher ratio of cell-free mitochondrial DNA (cf-mtDNA)/cell-free nuclear DNA compared with healthy controls. Additionally, mitochondrial DNA in patient samples showed significantly disproportionately increased hypomethylation compared with healthy controls, and it was increased further in crises compared with steady-state. Using flow cytometry, structured illumination microscopy, and electron microscopy, we showed that circulating SCD red blood cells abnormally retained their mitochondria and, thus, are likely to be the source of the elevated cf-mtDNA in patients with SCD. Patient plasma containing high levels of cf-mtDNA triggered the formation of neutrophil extracellular traps (NETs) that was substantially reduced by inhibition of TANK-binding kinase 1, implicating activation of the cGAS-STING pathway. cf-mtDNA is an erythrocytic DAMP, highlighting an underappreciated role for mitochondria in sickle pathology. These trials were registered at www.clinicaltrials.gov as #NCT00081523, #NCT03049475, and #NCT00047996.