Hu Zhongshuang, Murakami Taisuke, Suzuki Kaori, Tamura Hiroshi, Reich Johannes, Kuwahara-Arai Kyoko, Iba Toshiaki, Nagaoka Isao
Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan Laboratory Program Support (LPS) Consulting Office, Tokyo 160-0023, Japan.
Int Immunol. 2016 May;28(5):245-53. doi: 10.1093/intimm/dxv113. Epub 2016 Jan 7.
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 can modulate various inflammatory reactions. We previously revealed that LL-37 suppresses the LPS/ATP-induced pyroptosis of macrophages in vitro by both neutralizing the action of LPS and inhibiting the response of P2X7 (a nucleotide receptor) to ATP. Thus, in this study, we further evaluated the effect of LL-37 on pyroptosis in vivo using a cecal ligation and puncture (CLP) sepsis model. As a result, the intravenous administration of LL-37 improved the survival of the CLP septic mice. Interestingly, LL-37 inhibited the CLP-induced caspase-1 activation and pyroptosis of peritoneal macrophages. Moreover, LL-37 modulated the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in both peritoneal fluids and sera, and suppressed the activation of peritoneal macrophages (as evidenced by the increase in the intracellular levels of IL-1β, IL-6 and TNF-α). Finally, LL-37 reduced the bacterial burdens in both peritoneal fluids and blood samples. Together, these observations suggest that LL-37 improves the survival of CLP septic mice by possibly suppressing the pyroptosis of macrophages, and inflammatory cytokine production by activated macrophages and bacterial growth. Thus, the present findings imply that LL-37 can be a promising candidate for sepsis because of its many functions, such as the inhibition of pyroptosis, modulation of inflammatory cytokine production and antimicrobial activity.
LL-37是人类中唯一已知的抗微生物肽cathelicidin家族成员。除了具有广泛的抗微生物活性外，LL-37还可以调节各种炎症反应。我们之前发现，LL-37在体外通过中和LPS的作用和抑制P2X7（一种核苷酸受体）对ATP的反应来抑制LPS/ATP诱导的巨噬细胞焦亡。因此，在本研究中，我们使用盲肠结扎和穿刺（CLP）脓毒症模型进一步评估了LL-37对体内焦亡的影响。结果，静脉注射LL-37提高了CLP脓毒症小鼠的存活率。有趣的是，LL-37抑制了CLP诱导的腹膜巨噬细胞caspase-1激活和焦亡。此外，LL-37调节了腹膜液和血清中炎症细胞因子（IL-1β、IL-6和TNF-α）的水平，并抑制了腹膜巨噬细胞的激活（细胞内IL-1β、IL-6和TNF-α水平的增加证明了这一点）。最后，LL-37降低了腹膜液和血液样本中的细菌载量。总之，这些观察结果表明，LL-37可能通过抑制巨噬细胞焦亡、激活的巨噬细胞产生炎症细胞因子和细菌生长来提高CLP脓毒症小鼠的存活率。因此，本研究结果表明，由于LL-37具有多种功能，如抑制焦亡、调节炎症细胞因子产生和抗微生物活性，它可能是脓毒症的一个有前途的候选药物。
