Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113‑8421, Japan.
Microcoat Biotechnologie GmbH, D‑82347 Bernried, Germany.
Mol Med Rep. 2017 Oct;16(4):5618-5626. doi: 10.3892/mmr.2017.7267. Epub 2017 Aug 17.
LL‑37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL‑37 may modulate various inflammatory reactions. The authors previously revealed that LL‑37 improves the survival of a murine cecal ligation and puncture (CLP) sepsis model. In the present study, the mechanism for the protective action of LL‑37 was elucidated using the CLP model, focusing on the effect of LL‑37 on the release of neutrophil extracellular traps (NETs). The results indicated that the intravenous administration of LL‑37 suppressed the increase of damage-associated molecular patterns (DAMPs), including histone‑DNA complex and high‑mobility group protein 1, in addition to interleukin‑1β, tumor necrosis‑α and soluble triggering receptor expressed on myeloid cells (TREM)‑1 in plasma and peritoneal fluids. Notably, LL‑37 significantly suppressed the decrease of mononuclear cell number in blood, and the increase of polymorphonuclear cell (neutrophil) number in the peritoneal cavity during sepsis. Furthermore, LL‑37 reduced the bacterial burden in blood and peritoneal fluids. Notably, LL‑37 increased the level of NETs (myeloperoxidase‑DNA complex) in plasma and peritoneal fluids. In addition, it was verified that LL‑37 induces the release of NETs from neutrophils, and NETs possess the bactericidal activity. Overall, these observations suggest that LL‑37 improves the survival of CLP septic mice by possibly suppressing the inflammatory responses as evidenced by the inhibition of the increase of cytokines, soluble TREM‑1 and DAMPs (host cell death) and the alteration of inflammatory cell numbers, and bacterial growth via the release of NETs with bactericidal activity.
LL-37 是人类中唯一已知的抗菌肽 cathelicidin 家族成员。除了广谱的抗菌活性外，LL-37 还可能调节各种炎症反应。作者先前揭示了 LL-37 可改善小鼠盲肠结扎和穿刺 (CLP) 脓毒症模型的存活率。在本研究中，使用 CLP 模型阐明了 LL-37 的保护作用机制，重点研究了 LL-37 对中性粒细胞胞外诱捕网 (NETs) 释放的影响。结果表明，静脉内给予 LL-37 可抑制 DAMPs（包括组蛋白-DNA 复合物和高迁移率族蛋白 1）、白细胞介素-1β、肿瘤坏死-α 和可溶性髓样细胞触发受体 1（TREM-1）在血浆和腹腔液中的增加。值得注意的是，LL-37 显著抑制了脓毒症期间血液中单核细胞数量的减少和腹腔中多形核细胞（中性粒细胞）数量的增加。此外，LL-37 降低了血液和腹腔液中的细菌负荷。值得注意的是，LL-37 增加了血浆和腹腔液中 NETs（髓过氧化物酶-DNA 复合物）的水平。此外，验证了 LL-37 诱导中性粒细胞释放 NETs，并且 NETs 具有杀菌活性。综上所述，这些观察结果表明，LL-37 通过可能抑制细胞因子、可溶性 TREM-1 和 DAMPs（宿主细胞死亡）的增加以及炎症细胞数量和细菌生长的改变，通过释放具有杀菌活性的 NETs 来改善 CLP 脓毒症小鼠的存活率。
