Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Matthew Brook, Gareth H. Tomlinson, Katherine Miles, Richard W.P. Smith, Adriano G. Rossi, Pieter S. Hiemstra, Emily F.A. van 't Wout, Jonathan L. E. Dean, Nicola K. Gray, Wuyuan Lu, Mohini Gray

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)4350-4355
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number16
Early online date4 Apr 2016
Publication statusPublished - 19 Apr 2016


  • macrophages
  • α-defensins
  • mRNA translation
  • inflammation
  • cytokines


Dive into the research topics of 'Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation'. Together they form a unique fingerprint.

Cite this