Blocking the Toll-like receptor 9 (TLR9)/oxidized mitochondrial DNA axis may “prove to be a novel therapeutic strategy” for myelodysplastic syndromes (MDS), according to a recent study.
Grace A Ward, of the Cancer Biology PhD Program at the University of South Florida and H. Lee Moffitt Cancer Center & Research Institute, and colleagues conducted the research.
They previously reported that danger-associated molecular pattern oxidized mitochondrial DNA is “diagnostically increased in MDS plasma although the functional consequences remain poorly defined.”
“We hypothesized that [oxidized mitochondrial DNA] is released into the cytosol, upon NLRP3 and cryopyrin inflammasome pyroptotic lysis, where it propagates and further enhances the inflammatory cell death feed-forward loop onto healthy tissues,” the researchers wrote.
This can be mediated by oxidized mitochondrial DNA engagement of TLR9, an endosomal DNA sensing pattern recognition receptor “known to prime and activate the inflammasome propagating the [interferon]-induced inflammatory response in neighboring healthy hematopoietic stem and progenitor cells (HSPCs), which presents a potentially targetable axis for the reduction in inflammasome activation in MDS.”
The study showed extracellular oxidized mitochondrial DNA activates the TLR9-MyD88-inflammasome pathway, which was demonstrated by increased lysosome formation, interferon regulatory factor 7 translocation, and interferon-stimulated gene production. They also found that extracellular oxidized mitochondrial DNA induces TLR9 redistribution to the cell surface in MDS HSPCs.
The researchers validated the impact on NLRP3 inflammasome activation by using chemical inhibition to block TLR9 activation and knocking out TLR9 with CRISPR gene editing. These experiments demonstrated TLR9 was “necessary” for oxidized mitochondrial DNA-mediated inflammasome activation. Furthermore, lentiviral overexpression of TLR9 sensitized the cells to oxidized mitochondrial DNA and inhibiting TLR9 restored hematopoietic colony formation in MDS bone marrow.
“We conclude that MDS HSPCs are primed for inflammasome activation via [oxidized mitochondrial DNA] released by pyroptotic cells,” the researchers wrote. “Blocking the TLR9/[oxidized mitochondrial DNA] axis may prove to be a novel therapeutic strategy for MDS.”
Ward GA, Dalton RP 3rd, Meyer BS, et al. Oxidized mitochondrial DNA engages TLR9 to activate the NLRP3 inflammasome in myelodysplastic syndromes. Int J Mol Sci. 2023;24(4). doi:10.3390/ijms24043896