Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice

Hu, Zhongshuang; Murakami, Tatsuya; Suzuki, Kaori; Tamura, Hiroshi; Reich, Johannes; Kuwahara‐Arai, Kyoko; Iba, Toshiaki; Nagaoka, Isao

doi:10.1093/intimm/dxv113

Cited by 59 publications

(79 citation statements)

References 40 publications

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“…Interestingly, a previous study reported that Camp KO mice exhibit the increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture (CLP), an established experimental model of polymicrobial sepsis . However, another study showed that LL‐37 improves the survival of CLP septic mice possibly by suppressing the pyroptosis of macrophages, inflammatory cytokine production, and bacterial growth . These studies imply that cathelicidin has a complex role in the CLP septic model.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the therapeutic application of exogenous LL‐37 administration in sepsis has been widely investigated. These studies have shown that LL‐37 treatment protects mice against sepsis by suppressing apoptosis of endothelial cells, preventing intestinal barrier dysfunction, and inhibiting the pyroptosis of macrophages, inflammatory cytokine production, and bacterial growth . However, the influence of cathelicidin on septic cardiac defect is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Cathelicidin deficiency exacerbates cardiac dysfunction in lipopolysaccharide‐induced endotoxaemic mice

Zhai

Zhang

et al. 2020

Clin Exp Pharma Physio

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The therapeutic potential of the antimicrobial peptide cathelicidin (Camp) administration in sepsis has been widely investigated. However, little is known about the pathophysiological roles of cathelicidin in septic cardiomyopathy. In a lipopolysaccharide (LPS)‐induced endotoxaemic model, we found that the mRNA and protein expression of cardiac cathelicidin were induced in C57BL/6J wild‐type (WT) mice upon LPS challenge, accompanied by increased circulating cathelicidin levels. We showed that this peptide was mainly derived from neutrophils and monocytes/macrophages. Camp deficiency exacerbated LPS‐induced myocardial depression, while the administration of CRAMP (the mature form of mouse cathelicidin) decreased the LPS‐induced mortality in a D‐galactosamine hydrochloride (D‐GalN)‐sensitized endotoxin shock model. In vivo, LPS‐treated Camp knockout mice had a significant higher protein level of myocardial and circulating tumour necrosis factor‐alpha (TNF‐α), a major contributing factor to septic cardiomyopathy, compared to LPS‐treated WT mice, while CRAMP administration inhibited LPS‐induced TNF‐α production in the heart and plasma in D‐GalN‐sensitized endotoxaemic mice. In vitro, CRAMP treatment suppressed LPS‐induced Tnf‐α mRNA expression in cultured neonatal mouse cardiomyocytes and reduced TNF‐α secretion in the culture supernatant. The inhibitory effects of CRAMP on TNF‐α production may be related to its neutralizing ability of LPS, since CRAMP application had no effects on another toll‐like receptor 4 ligand paclitaxel‐induced Tnf‐α mRNA expression in cardiomyocytes. These findings suggest that LPS‐induced cathelicidin protects the heart against myocardial depression partly through the inhibition of TNF‐α production via neutralizing LPS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cathelicidin deficiency exacerbates cardiac dysfunction in lipopolysaccharide‐induced endotoxaemic mice

Zhai

Zhang

et al. 2020

Clin Exp Pharma Physio

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“…Ayres et al found that inflammasome activation in a mouse model of Escherichia coli resulted in IL-1β–driven lethal immunopathology, which could not be tolerated by the host34. Inhibiting inflammasome signaling and pyroptosis by caspase-1 specific inhibitors or caspase-1 and NLRC4 knockout also significantly alleviated tissue damage, decreased bacterial burden, and increased the survival rate of infected mice32333435.…”

Section: Discussionmentioning

confidence: 99%

Pyroptosis of Salmonella Typhimurium-infected macrophages was suppressed and elimination of intracellular bacteria from macrophages was promoted by blocking QseC

Zheng

Xue

et al. 2016

Sci Rep

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QseC is a membrane-bound histidine sensor kinase found in Gram-negative pathogens and is involved in the regulation of bacterial virulence. LED209, a QseC-specific inhibitor, significantly inhibits the virulence of several pathogens and partially protects infected mice from death by blocking QseC. However, the mechanism of its antibacterial effects remains unclear. In this experiment, a Salmonella Typhimurium (S. Typhimurium) and macrophage co-culture system was utilized to investigate possible mechanisms underlying the antimicrobial effects of the QseC inhibitor. QseC blockade inhibited the expression of QseC-dependent virulence genes, including flhDC, sifA, and sopB, in S. Typhimurium, leading to inhibition of swimming motility, invasion capacity, and replication capacity of the pathogens. Release of lactate dehydrogenase (LDH) from S. Typhimurium-infected macrophages was significantly inhibited by blocking QseC. Activated caspase-1 and IL-1β levels were suppressed, and intracellular bacterial count was reduced in infected macrophages. QseC blockade effectively reduced the virulence of S. Typhimurium, inhibited S. Typhimurium-induced pyroptosis of macrophages, and promoted elimination of intracellular bacteria from infected macrophages. Thus, the antibacterial effects of QseC inhibitor are mediated via enhancement of intracellular killing of S. Typhimurium in macrophages.

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“…Of note, the administration of LL-37 significantly suppressed the CLP-induced caspase-1 activation and pyroptosis of peritoneal macrophages ( Figure-4B and C). Moreover, LL-37 modulated the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) both in the peritoneal fluids and sera and suppressed the activation of peritoneal macrophages (as evaluated by the increase in the intracellular levels of IL-1β, IL-6 and TNF-α) 31) . Furthermore, LL-37 reduced the bacterial burdens both in peritoneal fluids and blood samples 31) .…”

Section: Inhibition Of the Macrophage Pyroptosis And Improvement Of Tmentioning

confidence: 96%

“…Moreover, LL-37 modulated the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) both in the peritoneal fluids and sera and suppressed the activation of peritoneal macrophages (as evaluated by the increase in the intracellular levels of IL-1β, IL-6 and TNF-α) 31) . Furthermore, LL-37 reduced the bacterial burdens both in peritoneal fluids and blood samples 31) . Thus, our present study suggests that LL-37 improves the survival of CLP septic mice by possibly suppressing the pyroptosis of macrophages, and inflammatory cytokine production by activated macrophages as well as bacterial growth (Figure-5, right panel).…”

Section: Inhibition Of the Macrophage Pyroptosis And Improvement Of Tmentioning

confidence: 96%

Modulation of Macrophage Cell Death, Pyroptosis by Host Defense Peptide LL-37

Nagaoka

2016

Juntendo Medical Journal

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Pyroptosis is defined as a caspase-1 dependent cell death and mainly occurs in macrophages and dendritic cells, accompanied with the release of pro-inflammatory cytokines. Moreover, pyroptosis results in the cellular lysis and release of cytosolic contents, which induce the augmentation of inflammatory reactions. Of note, caspase-1 knockout (KO) causes a protective effect on the sepsis models and improves the survival of mice, in which the IL-1β level was totally suppressed. Thus, caspase-1 activation and possibly pyroptosis play a major role in the mortality of sepsis. AMPs (antimicrobial peptides) are functioning in the first line of defense against invading pathogens. Cathelicidin family of AMPs are recognized in many mammalian species, and LL-37 is the only one human cathelicidin. Besides its broad spectrum of antimicrobial actions, LL-37 has a role in innate immune defense, such as regulation of inflammatory responses and wound healing. Interestingly, LL-37 displays the protective effect on the endotoxemia models. In this review, we introduce a newly identified inhibitory effect of LL-37 on macrophage pyroptosis in vitro and in vivo.

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Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice

Cited by 59 publications

References 40 publications

Cathelicidin deficiency exacerbates cardiac dysfunction in lipopolysaccharide‐induced endotoxaemic mice

Cathelicidin deficiency exacerbates cardiac dysfunction in lipopolysaccharide‐induced endotoxaemic mice

Pyroptosis of Salmonella Typhimurium-infected macrophages was suppressed and elimination of intracellular bacteria from macrophages was promoted by blocking QseC

Modulation of Macrophage Cell Death, Pyroptosis by Host Defense Peptide LL-37

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