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Updated: Mar 23, 2026
Highly Efficient Transfection of Primary Macrophages with In Vitro Transcribed mRNA
Published on: November 9, 2019
Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation
Matthew Brook1, Gareth H Tomlinson2, Katherine Miles2
1Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
Abstract:
Neutrophils are the first and most numerous cells to arrive at the site of an inflammatory insult and are among the first to die. We previously reported that alpha defensins, released from apoptotic human neutrophils, augmented the antimicrobial capacity of macrophages while also inhibiting the biosynthesis of proinflammatory cytokines. In vivo, alpha defensin administration protected mice from inflammation, induced by thioglychollate-induced peritonitis or following infection withSalmonella entericaserovar Typhimurium. We have now dissected the antiinflammatory mechanism of action of the most abundant neutrophil alpha defensin, Human Neutrophil Peptide 1 (HNP1). Herein we show that HNP1 enters macrophages and inhibits protein translation without inducing the unfolded-protein response or affecting mRNA stability. In a cell-free in vitro translation system, HNP1 powerfully inhibited both cap-dependent and cap-independent mRNA translation while maintaining mRNA polysomal association. This is, to our knowledge, the first demonstration of a peptide released from one cell type (neutrophils) directly regulating mRNA translation in another (macrophages). By preventing protein translation, HNP1 functions as a "molecular brake" on macrophage-driven inflammation, ensuring both pathogen clearance and the resolution of inflammation with minimal bystander tissue damage.
Insights
Human Neutrophil Peptide 1 (HNP1), released by dying neutrophils, acts as a molecular brake by inhibiting protein translation in macrophages. This anti-inflammatory mechanism ensures pathogen clearance while minimizing tissue damage.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Neutrophils are key early responders to inflammation, releasing alpha defensins upon apoptosis.
- Alpha defensins, like Human Neutrophil Peptide 1 (HNP1), have shown antimicrobial and anti-inflammatory properties in previous studies.
- HNP1 is the most abundant alpha defensin released by neutrophils.
Purpose of the Study:
- To elucidate the anti-inflammatory mechanism of Human Neutrophil Peptide 1 (HNP1).
- To investigate how HNP1 regulates macrophage function during inflammation.
Main Methods:
- HNP1 was administered to macrophages to assess its cellular effects.
- Protein translation inhibition was measured in vitro using a cell-free system.
- Effects on mRNA stability and the unfolded protein response were evaluated.
Main Results:
- HNP1 entered macrophages and inhibited protein translation.
- HNP1 suppressed both cap-dependent and cap-independent mRNA translation.
- HNP1 maintained mRNA polysomal association during translation inhibition.
- HNP1 did not induce the unfolded protein response or affect mRNA stability.
Conclusions:
- HNP1 acts as a novel regulator of macrophage function by directly inhibiting protein translation.
- This mechanism serves as a "molecular brake" to control inflammation, balancing pathogen clearance with tissue protection.
- This represents the first demonstration of a neutrophil-derived peptide directly regulating mRNA translation in macrophages.
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