Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model.

Isao Nagaoka,Hiroshi Tamura,Johannes Reich

doi:10.3390/ijms21175973

Isao Nagaoka, Hiroshi Tamura + Show 1 more

Open Access

https://doi.org/10.3390/ijms21175973

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Abstract

Among the mechanisms put-up by the host to defend against invading microorganisms, antimicrobial peptides represent the first line. In different species of mammals, the cathelicidin family of antimicrobial peptides AMPs has been identified, and in humans, LL-37 is the only type of cathelicidin identified. LL-37 has many different biological activities, such as regulation of responses to inflammation, besides its lipopolysaccharide (LPS)-neutralizing and antimicrobial and activities. Recently, employing a murine septic model that involves cecal ligation and puncture (CLP), we examined the effect of LL-37. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, the survival of CLP mice was found to be improved by LL-37 by the suppression of the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, the release of neutrophil extracellular traps (NETs), which have potent bactericidal activity, is enhanced by LL-37, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), which improve the pathological condition of sepsis. These findings indicate that LL-37 protects CLP septic mice through at least three mechanisms, i.e., the suppression of pro-inflammatory macrophage pyroptosis and the release of antimicrobial NETs (induction of NETosis) and ectosomes from neutrophils. Thus, LL-37 can be a potential therapeutic candidate for sepsis due to its multiple properties, including the modulation of cell death (pyroptosis and NETosis) and the release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities.

Highlights

Sepsis is a frequent cause of mortality in the noncoronary intensive care unit (ICU)
We described that the LPS/ATP-induced pyroptosis as well as production of IL-1β are suppressed by LL-37 in macrophages by both curtailing the effect of LPS on CD14/TLR4 (Toll-like receptor 4) and preventing the P2X7 response to ATP in vitro [40]
The results indicated that the administration of LL-37 (2 μg/mouse) intravenously, to the cecal ligation and puncture (CLP) septic mice, improves their survival (Figure 4), and the effect was dose-dependent, since LL-37

Summary

Introduction

Sepsis is a frequent cause of mortality in the noncoronary intensive care unit (ICU). Sepsis model and revealed that the survival of CLP septic mice is improved by the administration of LL-37, which caused the suppression of macrophage pyroptosis [32] and the release of NETs [33]. N-terminal fragments, membrane due to their binding to certain lipids in the plasma membrane inner leaflet, leading to the generated activated caspases, and create poresCaspase-4/-5/-11, in the plasma membrane due tohand, their release of by cellular contents and oligomerize cell death (violet arrows). (1 the pyroptosis of peritoneal macrophages and the CLP-induced caspase-1 activation are inhibited by μg/mouse and 2 μg/mouse) improved the survival rate to 14.3% and 36.4%, respectively [32]. Levels the levels of inflammatory and Interestingly, the pyroptosis of peritoneal macrophages and the CLP-induced caspase-1 activation the peritoneal fluids sera were reduced.

Effect

Effect fluids of LL-37 on the levels of HMGB1 and histone-DNA complex

14. Antibacterial

Perspective

Findings

16. Therapeutic