LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.
Nat Cell Biol
; 24(12): 1701-1713, 2022 12.
Article
in En
| MEDLINE
| ID: mdl-36474072
ABSTRACT
Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.
Full text:
1
Database:
MEDLINE
Main subject:
Toll-Like Receptor 8
/
Macrophages
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nat Cell Biol
Year:
2022
Type:
Article
Affiliation country:
United States