Inhibition of mevalonate pathway by macrophage‐specific delivery of atorvastatin prevents their pro‐inflammatory polarisation

Adjustment of the cellular metabolism of pro‐inflammatory macrophages is essential for their bactericidal function; however, it underlies the development of many human diseases if induced chronically. Therefore, intervention of macrophage metabolic polarisation has been recognised as a potent strate...

Full description

Saved in:
Bibliographic Details
Published in:Insect molecular biology 2024-08, Vol.33 (4), p.323-337
Main Authors: Krejčová, Gabriela, Ruphuy, Gabriela, Šalamúnová, Petra, Sonntag, Erik, Štěpánek, František, Bajgar, Adam
Format: Article
Language:English
Subjects:
Atorvastatin
Glucan
glucan particles
Hydroxymethylglutaryl-CoA reductase
In vivo methods and tests
Inhibitors
Macrophages
macrophage‐specific delivery
Mevalonate pathway
Polarization
Reductases
Side effects
Yeasts
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Adjustment of the cellular metabolism of pro‐inflammatory macrophages is essential for their bactericidal function; however, it underlies the development of many human diseases if induced chronically. Therefore, intervention of macrophage metabolic polarisation has been recognised as a potent strategy for their treatment. Although many small‐molecule inhibitors affecting macrophage metabolism have been identified, their in vivo administration requires a tool for macrophage‐specific delivery to limit their potential side effects. Here, we establish Drosophila melanogaster as a simple experimental model for in vivo testing of macrophage‐specific delivery tools. We found that yeast‐derived glucan particles (GPs) are suitable for macrophage‐specific delivery of small‐molecule inhibitors. Systemic administration of GPs loaded with atorvastatin, the inhibitor of hydroxy‐methyl‐glutaryl‐CoA reductase (Hmgcr), leads to intervention of mevalonate pathway specifically in macrophages, without affecting HMGCR activity in other tissues. Using this tool, we demonstrate that mevalonate pathway is essential for macrophage pro‐inflammatory polarisation and individual's survival of infection. GPs act as a tool for macrophage‐specific delivery of inhibitors. Increased activity of Hmgcr is essential for the survival of bacterial infection. Drosophila is suitable for investigating the effects of metabolic inhibitors.
ISSN:0962-1075
1365-2583
1365-2583
DOI:10.1111/imb.12900