title: Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation.
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.
authors.affiliation: Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Matthew
authors.identifier: http://orcid.org/0000-0003-1245-7385
authors.initials: M
authors.lastname: Brook
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Gareth H
authors.initials: GH
authors.lastname: Tomlinson
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Katherine
authors.initials: K
authors.lastname: Miles
authors.affiliation: Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Richard W P
authors.initials: RW
authors.lastname: Smith
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands;
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands;
authors.forename: Emily F A
authors.initials: EF
authors.lastname: van 't Wout
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom;
authors.forename: Jonathan L E
authors.initials: JL
authors.lastname: Dean
authors.affiliation: Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland;
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Gray
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland; mohini.gray@ed.ac.uk.
authors.forename: Mohini
authors.initials: M
authors.lastname: Gray
mesh_terms: D000818:Animals; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D012480:Salmonella Infections / Q000378:metabolism* / Q000473:pathology; D012486:Salmonella typhimurium; D023084:alpha-Defensins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D023084:alpha-Defensins; C406413:human neutrophil peptide 1
keywords: cytokines; inflammation; mRNA translation; macrophages; α-defensins