Therapeutic Action of Antimicrobial Cathelicidin Peptide LL-37 on a Murine Sepsis Model

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  • NAGAOKA ISAO
    Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine
  • HU ZHONGSHUANG
    Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine
  • HOSODA HIROSHI
    Department of Molecular Microbiology, Faculty of Life Sciences, Tokyo University of Agriculture
  • KUMAGAI YUMI
    Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine

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Abstract

<p>　Antimicrobial peptides (AMPs) represent the first line of host defense against invading microorganisms. Cathelicidin family of AMPs has been identified in various mammalian species, and LL-37 is the only cathelicidin identified in humans. In addition to its antimicrobial and lipopolysaccharide (LPS)-neutralizing activities, LL-37 exhibits diverse biological activities, including regulation of inflammatory responses. Recently, we have evaluated the effect of LL-37 on a murine cecal ligation and puncture (CLP) septic model. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, LL-37 improves the survival of CLP mice by suppressing the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, LL-37 induces the release of neutrophil extracellular traps (NETs) with potent bactericidal activity, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), thereby improving murine sepsis. These observations suggest 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 promising therapeutic candidate for sepsis because of its multiple functions, including the modulation of cell death (pyroptosis and NETosis) and release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities.</p>

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