Dataset Information

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

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.

SUBMITTER: Allen RM

PROVIDER: S-EPMC10609361 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

Allen Ryan M RM Michell Danielle L DL Cavnar Ashley B AB Zhu Wanying W Makhijani Neil N Contreras Danielle M DM Raby Chase A CA Semler Elizabeth M EM DeJulius Carlisle C Castleberry Mark M Zhang Youmin Y Ramirez-Solano Marisol M Zhao Shilin S Duvall Craig C Doran Amanda C AC Sheng Quanhu Q Linton MacRae F MF Vickers Kasey C KC

Nature cell biology 20221206 12

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) ...[more]

PMID: 36474072

Similar Datasets

Project description:Background: Arteriosclerosis (AS) involves arterial inflammation. Using macrophage-based drug delivery system, we aim to enhance local drug concentration, especially for short-lived anti-inflammatory molecules like interleukin-10. Our study intervenes in plaque progression by boosting IL-10 expression in macrophages lentiviral transfection and introducing these anti-inflammatory cells into Apoe-/- mice. Methods: We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirus vectors. Subsequent in vitro experiments were conducted to validate the effects and cellular functions of IL-10M. Fluorescence imaging allowed us to track the localization of IL-10M at atherosclerotic plaque sites after intravenous (IV) injection in Apoe-/- mice. We administered periodic injections of IL-10M at different stages of plaque progression in AS mice to assess its therapeutic impact on plaque advancement. Following the intervention, we collected samples from major organs and serum to evaluate the safety of IL-10M treatment. Results: Our engineered IL-10M exhibits robust IL-10 secretion, maintaining macrophage phagocytic function, and showing a tendency toward an M2 phenotype when exposed to inflammatory stimuli. Upon intravenous IL-10M administration, fluorescence imaging highlights precise plaque localization in both global and cross-sectional aortic regions. Regardless of whether intervention is initiated early or late in plaque progression, we observe significant reductions in plaque area and necrotic core. Importantly, IL-10M intervention does not impact the histological characteristics of the heart, liver, spleen, lungs, and kidneys, nor does it influence systemic inflammation levels. Conclusion: Our team has devised a novel anti-inflammatory protein delivery system utilizing modified macrophages, which exhibit a remarkable ability to target atherosclerotic plaques, resulting in the reduction of both plaque area and necrotic core. This innovative approach demonstrates favorable safety profiles and holds significant potential as a therapeutic strategy for managing atherosclerosis.

Dataset Information

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

Publications

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets