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

• Published in: International journal of molecular sciences 2020-08, Vol.21 (17), p.5973
• Main Authors: Nagaoka, Isao, Tamura, Hiroshi, Reich, Johannes
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antiinfectives and antibacterials; Antimicrobial agents; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - therapeutic use; antimicrobial peptide; Antimicrobial peptides; Apoptosis; Bacteria; Bacterial infections; Bactericidal activity; cathelicidin; Cecum; Cell death; Cytokines; Dendritic cells; Deoxyribonucleic acid; DNA; ectosome; IL-1β; Inflammation; Leukocytes (neutrophilic); Lipopolysaccharides; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Mice; Microorganisms; Mortality; NETs; Neutralizing; Neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Peptides; Plasma; Proteins; Pyroptosis; Review; Sepsis; Sepsis - drug therapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21175973

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.