Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 16, Pages 4350-4355Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1601831113
Keywords
macrophages; alpha-defensins; mRNA translation; inflammation; cytokines
Categories
Funding
- Arthritis Research UK [18722]
- Medical Research Council (MRC) [MR/J009555/1]
- MRC [MR/J003069/1]
- BBSRC [BB/J01687X/1] Funding Source: UKRI
- MRC [MR/J009555/1, G0901697, MR/J003069/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J01687X/1] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20035] Funding Source: researchfish
- Medical Research Council [G0901697, MR/J009555/1, MR/J003069/1] Funding Source: researchfish
Ask authors/readers for more resources
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 with Salmonella enterica serovar 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available