Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease

Laxminath Tumburu, Shohini Ghosh-Choudhary, Fayaz T. Seifuddin, Emilia A. Barbu, Simon Yang, Maliha M. Ahmad, Lauren H.W. Wilkins, Ilker Tunc, Ishwarya Sivakumar, James S. Nichols, Pradeep K. Dagur, Shutong Yang, Luis E.F. Almeida, Zenaide M.N. Quezado, Christian A. Combs, Eric Lindberg, Christopher K.E. Bleck, Jun Zhu, Arun S. Shet, Jay H. ChungMehdi Pirooznia, Swee Lay Thein

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish
Pages (from-to)3116-3126
Number of pages11
JournalBlood
Volume137
Issue number22
DOIs
StatePublished - 3 Jun 2021
Externally publishedYes

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