Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation.
Ke-Ying ZhuYang WangHeela SarlusKeyi GengErik NutmaJingxian SunShin-Yu KungCindy BayJinming HanJin-Hong MinIrene Benito-CuestaHarald LundSandra AmorJun WangXing-Mei ZhangClaudia KutterAndre Ortlieb Guerreiro-CacaisBjörn HögbergRobert A HarrisPublished in: EMBO reports (2022)
Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase 1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS-challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using β-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS-like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid-specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells.
Keyphrases
- inflammatory response
- induced apoptosis
- multiple sclerosis
- bone marrow
- dendritic cells
- cell cycle arrest
- acute myeloid leukemia
- lipopolysaccharide induced
- traumatic brain injury
- cell death
- endoplasmic reticulum stress
- stem cells
- single cell
- emergency department
- type diabetes
- mesenchymal stem cells
- single molecule
- cell proliferation
- toll like receptor
- cell free
- circulating tumor
- molecular docking
- cell therapy
- immune response
- adipose tissue
- mouse model
- radiation therapy
- radiation induced
- white matter
- spinal cord
- heat stress
- cerebral ischemia