What question did this study set out to answer?

To determine how oxidized mitochondrial DNA released during pyroptosis drives NLRP3 inflammasome activation and propagation in myelodysplastic syndromes.

February 15, 2023International Journal of Molecular SciencesOpen Access

Oxidized Mitochondrial DNA Engages TLR9 to Activate the NLRP3 Inflammasome in Myelodysplastic Syndromes

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Authors

GWGrace WardMoffitt Cancer Center RDRobert DaltonMoffitt Cancer Center BMBenjamin S. MeyerUniversity of Florida

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Implication

Preclinical study demonstrates that oxidized mitochondrial DNA activates TLR9 to drive NLRP3 inflammasome-mediated cell death in myelodysplastic syndromes, highlighting a potential therapeutic target.

Key Points

To determine how oxidized mitochondrial DNA released during pyroptosis drives NLRP3 inflammasome activation and propagation in myelodysplastic syndromes.
Treated myelodysplastic syndrome hematopoietic stem and progenitor cells with extracellular oxidized mitochondrial DNA and monitored lysosome formation, IRF7 translocation, and interferon-stimulated gene production.
Manipulated TLR9 activity using pharmacological inhibitors, CRISPR knockout, and lentiviral overexpression to evaluate its necessity in inflammasome activation.
Assessed the functional impact of TLR9 inhibition on hematopoietic colony formation in myelodysplastic syndrome bone marrow.
Extracellular oxidized mitochondrial DNA triggered the TLR9-MyD88 pathway and induced redistribution of TLR9 to the cell surface in hematopoietic stem and progenitor cells.
TLR9 knockout and chemical inhibition prevented oxidized mitochondrial DNA-driven inflammasome activation, whereas TLR9 overexpression sensitized cells to activation.
Inhibition of TLR9 successfully restored hematopoietic colony-forming capacity in myelodysplastic syndrome bone marrow.

Cite This Study

Ward et al. (2023) studied this question.

synapsesocial.com/papers/69dd467eac7bdbc6c7101604 https://doi.org/10.3390/ijms24043896

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Oxidized Mitochondrial DNA Engages TLR9 to Activate the NLRP3 Inflammasome in Myelodysplastic Syndromes

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Implication

Key Points

Cite This Study

Oxidized Mitochondrial DNA Engages TLR9 to Activate the NLRP3 Inflammasome in Myelodysplastic Syndromes

Discussion

Member takes

Implication

Key Points

Cite This Study

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