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 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.

Expression and Function of Host Defense Peptides at Inflammation Sites

“…To illustrate, these peptides not only attract immune cells, e.g., neutrophils, but also by blocking apoptosis prolong their lifespan, and in turn phagocytic functions [81]. On the other hand, HDPs may function as a "molecular brake" on macrophage-driven inflammation to maximize eradication of pathogens with minimal adverse effects on surrounding tissues [82].…”

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

“…There is increasing evidence for neutrophil heterogeneity and plasticity in terms of cellular responses and surface expression of receptors, with both pro and anti-inflammatory subpopulations described (figure 3) [141,142]. An anti-inflammatory and pro-resolving neutrophil phenotype have been described, where the secretion of α-defensins modifies the inflammatory response of macrophages [143] and neutrophils can also modify angiogenic processes with the secretion of MMP-9 [144], as well as their typical proinflammatory responses. It is unclear whether the presence of chronic inflammatory disease in an ageing host leads to a loss of neutrophil plasticity, a change in phenotype or merely a priming of cells, but there is clear evidence of increased neutrophil activity and dysfunction across COPD, atherosclerosis and T2D (as described earlier) and studies are describing differences in neutrophil populations between patients with COPD and controls [145] and in murine models of atherosclerosis [146], although this field is in its infancy.…”

Extracellular vesicles regulate immune responses and cellular function in intestinal inflammation and repair

“…However, emerging evidence demonstrates increased PMN plasticity, life-span, and phenotypic heterogeneity in inflamed tissues. 12 As such, in addition to their phagocytic activity that protects against pathogens and removes apoptotic/ necrotic cells and cellular debris, PMNs are capable of producing a milieu of pro-resolving mediators, including antibacterial peptides, 13 resolvins, 14 defensins, 15 and cationic peptides such as LL-37, 16 nitric oxide, 17 and transforming growth factor beta (TGFb) 18 in order to promote epithelial repair. 19 PMNs can further physically interact with epithelial receptors such as intercellular adhesion molecule-1 (ICAM-1) to direct IEC proliferation, 20 repair of blood vessels, 21 and sequential recruitment of pro-resolving macrophages to assist wound closure.…”