Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease

Abstract

The pathophysiology of sickle cell disease (SCD) is driven by chronic inflammation. We show that elevated cell-free DNA (cfDNA) in SCD patients is not just a prognostic biomarker but contributes to the pathological inflammation. Within the elevated cfDNA, SCD patients had significantly higher proportion of mitochondrial (cf-mtDNA) to nuclear cfDNA (cf-nDNA) compared to healthy controls. Additionally, mtDNA in patient samples showed significant disproportionately increased hypomethylation compared to healthy controls, that was further increased in crises when compared to 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 likely to be the source of the elevated cf-mtDNA in SCD patients. Patient plasma containing high levels of cf-mtDNA triggered formation of neutrophil extracellular traps (NETs) that was substantially reduced by inhibition of TANK-binding kinase 1 (TBK1) implicating activation of the cGAS-STING pathway. cf-mtDNA is an erythrocytic-DAMP, highlighting an underappreciated role of mitochondria in sickle pathology. Clinicaltrials.gov identifiers: #NCT00081523, #NCT03049475, #NCT00047996

Dysfunctional telomeres through mitostress‐induced cGAS/STING activation to aggravate immune senescence and viral pneumonia

“…It is noted that in addition to virus‐derived molecules such as viral proteins, DNA, and RNA, innate immune cells also recognize and react to the “danger” signals that are released from stressed and senescent cells. With aging, cells undergo profound functional alteration involving replicative exhaustion, DNA damage, redox imbalance, and oncogenic activation, which may in turn trigger the release of damage‐associated molecular patterns (DAMPs) such as HMGB1, ATP, and mitochondrial DNA (mtDNA) to activate innate immune cells via PRRs (Tumburu et al, 2021). Among these changes, age‐related impairment in mitochondrial quality control is considered a key event contributing to exacerbated inflammation.…”

Transfusional Approach in Multi-Ethnic Sickle Cell Patients: Real-World Practice Data From a Multicenter Survey in Italy

“…In contrast, African SCD patients were mainly clustered in pediatric and young adult populations, reflecting the voluntary migration fluxes of the last two decades ( 22 , 23 , 31 ). Indeed, the presence of elderly Caucasian SCD patients represents a unique SCD cohort, providing important information on the combinatory effects of aging and SCD on disease natural history ( 32 , 33 ).…”

Molecular Mechanisms of mtDNA-Mediated Inflammation

“…The increase in cf-mtDNA levels was suggested to trigger the activation of NETs formation and cGAS-STING pathway. The authors reported mitochondrial retention by circulating SCD red blood cells and suggested that this could be the source of the elevated levels of cf-mtDNA [ 99 ]. Two mechanisms have been proposed to explain how mtDNA is released in the extracellular space.…”