Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease
| Autor: | Laxminath Tumburu, Mehdi Pirooznia, Arun S. Shet, Luis E.F. Almeida, James S. Nichols, Jun Zhu, Eric Lindberg, Maliha Maryam Ahmad, Christopher K. E. Bleck, Ilker Tunc, Ishwarya Sivakumar, Christian A. Combs, Emilia Alina Barbu, Fayaz Seifuddin, Lauren H. W. Wilkins, Swee Lay Thein, Shohini Ghosh-Choudhary, Shutong Yang, Simon Yang, Pradeep K. Dagur, Zenaide M.N. Quezado, Jay H. Chung |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Mitochondrial DNA
Erythrocytes business.industry Immunology Inflammation Cell Biology Hematology Neutrophil extracellular traps Anemia Sickle Cell Mitochondrion medicine.disease Biochemistry Sickle cell anemia Pathophysiology Proinflammatory cytokine Red Cells Iron and Erythropoiesis Cell-free fetal DNA medicine Humans medicine.symptom business |
| Zdroj: | Blood |
| ISSN: | 0008-1523 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|