Leukotriene B4 Induces Release of Antimicrobial Peptides in Lungs of Virally Infected Mice

Abstract

Leukotriene B4 (LTB4) is a lipid mediator of inflammation that was recently shown to exert antiviral activities. In this study, we demonstrate that the release of antimicrobial proteins by neutrophils contribute to an early host defense against influenza virus infection in vitro as well as in vivo. Daily i.v. treatments with LTB4 lead to a significant decrease in lung viral loads at day 5 postinfection in mice infected with influenza A virus compared with the placebo-treated group. This reduction in viral load was not present in mice deficient in the high-affinity LTB4 receptor. Viral clearance in lungs was associated with up-regulated presence of antimicrobial peptides such as β-defensin-3, members of the mouse eosinophil-related RNase family, and the mouse cathelicidin-related antimicrobial peptide. Our results also indicate that neutrophils are important in the antiviral effect of LTB4. Viral loads in neutrophil-depleted mice were not diminished by LTB4 administration, and a substantial reduction in the presence of murine cathelicidin-related antimicrobial peptide and the murine eosinophil-related RNase family in lung tissue was observed. Moreover, in vitro treatment of human neutrophil cultures with LTB4 led rapidly to the secretion of the human cathelicidin LL-37 and eosinophil-derived neurotoxin, known as antiviral peptides. Pretreatment of cell cultures with specific LTB4 receptor antagonists clearly demonstrate the implication of the high-affinity LTB4 receptor in the LTB4-mediated activity. Together, these results demonstrate the importance of neutrophils and the secretion of antimicrobial peptides during the early immune response mediated by LTB4 against a viral pathogen.

2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV

“…We indeed documented that 2-AG was rapidly hydrolyzed to AA and further converted into LTB 4 by human neutrophils [36]. Given that LTB 4 promotes the ingestion and killing of microbes and the release of antimicrobial peptides [38][39][40][41][42], we postulated that 2-AG and AA would have similar effects. In this study, we investigated the antimicrobial activities of human neutrophils activated by 2-AG or AA.…”

Leukotriene B₄, an Endogenous Stimulator of the Innate Immune Response against Pathogens

“…Daily administration of LTB 4 to influenza-infected mice potentiated the reduction of lung viral loads as opposed to mice treated with a placebo [42]. Results from this study indicate that recruitment of neutrophils to the lungs is an important event in controlling influenza infection, which correlates with a decrease in viral load and restored lung architecture.…”

“…Cathelicidins are thought to neutralize LPS found on bacteria. Finally, eosinophil-derived neurotoxin and its murine homologue mouse eosinophil-associated RNase are two RNases with antiviral activity against respiratory viruses [42]. In fact, secretion of antimicrobial peptides by neutrophils was found to contribute to the antiviral activities of LTB 4 against influenza virus [42].…”

Expression of hBD-2 induced by 23-valent pneumococcal polysaccharide vaccine, Haemophilus influenzae type b vaccine and split influenza virus vaccine

“…Besides microorganisms, LTB4, L12, L23, L27 and certain other immune factors also induce the expression of hBD-2 (24,28). However, using these microorganisms to study the regulation and function in vivo and in vitro often leads to the threat of a biological hazard.…”

“…Since the discovery of natural antimicrobial peptides, much research has been carried out to improve the innate immune response, including the study of many gene-based therapies (19)(20)(21)(22)(23)(24). However, to date, all these methods are under preliminary investigation, and no new clinical application has been proposed.…”