Antimicrobial peptide LL-37 ameliorates a murine sepsis model via the induction of microvesicle release from neutrophils

• Published in: Innate immunity (London, England) Vol. 26; no. 7; pp. 565 - 579
• Main Authors: Kumagai, Yumi, Murakami, Taisuke, Kuwahara-Arai, Iba, Toshiaki, Reich, Johannes, Nagaoka, Isao
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-10-2020; SAGE PUBLICATIONS, INC; SAGE Publishing
• Subjects: Antibacterial activity; Antimicrobial agents; Antimicrobial peptides; Bacteria; Bone marrow; Cecum; Inflammation; Leukocytes (neutrophilic); Neutrophils; Original; Peptides; Sepsis; antibacterial activity; Sepsis; antimicrobial peptide LL-37; neutrophil; ectosome
• ISSN: 1753-4259; 1753-4267
• DOI: 10.1177/1753425920936754

Sepsis is a life-threatening disease caused by systemic dys-regulated inflammatory response to infection. We previously revealed that LL-37, a human cathelicidin antimicrobial peptide, improves the survival of cecal ligation and puncture septic mice. Ectosomes, microvesicles released from neutrophils, are reported to be elevated in sepsis survivors; however, the functions of ectosomes in sepsis remain largely unknown. Therefore, we herein elucidated the protective action of LL-37 on sepsis, by focusing on LL-37-induced ectosome release in a cecal ligation and puncture model. The results demonstrated the enhancement of ectosome levels by LL-37 administration, accompanied by a reduction of bacterial load. Importantly, ectosomes isolated from LL-37-injected cecal ligation and puncture mice contained higher amounts of antimicrobial proteins/peptides and exhibited higher antibacterial activity, compared with those from PBS-injected cecal ligation and puncture mice, suggesting that LL-37 induces the release of ectosomes with antibacterial potential in vivo. Actually, LL-37 stimulated mouse bone-marrow neutrophils to release ectosomes ex vivo, and the LL-37-induced ectosomes possessed antibacterial potential. Furthermore, administration of LL-37-induced ectosomes reduced the bacterial load and improved the survival of cecal ligation and puncture mice. Together these observations suggest LL-37 induces the release of antimicrobial ectosomes in cecal ligation and puncture mice, thereby reducing the bacterial load and protecting mice from lethal septic conditions.