MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages
Francesco R Luly1, Manuella Lévêque1,2, Valerio Licursi1
1Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy.
Abstract:
Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.
Insights
MicroRNAs (miRNAs) play a role in cystic fibrosis (CF) macrophage dysfunction. This study found that miR-146a overexpression in CF macrophages restricts inflammatory responses, suggesting a potential therapeutic target for CF-related inflammation.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Cystic fibrosis (CF) is an inherited disorder characterized by impaired host defense and chronic lung inflammation.
- Macrophages in CF patients exhibit reduced bacterial killing and exaggerated inflammatory responses, but underlying mechanisms are unclear.
- MicroRNAs (miRNAs) are critical regulators of macrophage function, including inflammatory responses.
Purpose of the Study:
- To investigate if miRNA dysregulation contributes to the functional abnormalities observed in CF macrophages.
- To identify specific miRNAs involved in CF macrophage dysfunction.
- To elucidate the role of miR-146a in regulating inflammatory responses in CF macrophages.
Main Methods:
- Performed miRNA profiling on macrophages from CF and non-CF individuals.
- Identified differentially expressed miRNAs using bioinformatics analysis.
- Investigated the functional impact of miR-146a modulation on inflammatory cytokine production in lipopolysaccharide-stimulated CF macrophages.
Main Results:
- Identified 22 differentially expressed miRNAs between CF and non-CF macrophages.
- miR-146a was significantly dysregulated and associated with inflammation-related genes.
- Inhibition of miR-146a in CF macrophages led to increased interleukin-6 production, indicating a functional role in restricting inflammation.
Conclusions:
- MiRNA dysregulation, particularly miR-146a, contributes to CF macrophage functional abnormalities.
- Overexpression of miR-146a in CF macrophages serves to limit inflammatory responses.
- Targeting miR-146a may offer a therapeutic strategy for managing CF-related inflammation.
