Novel Role of the Antimicrobial Peptide LL-37 in the Protection of Neutrophil Extracellular Traps against Degradation by Bacterial Nucleases

Neumann, Ariane; Völlger, Lena; Berends, Evelien T.M.; Molhoek, E. Margo; Stapels, Daphne A. C.; Midon, Marika; Friães, Ana; Pingoud, Alfred; Rooijakkers, Suzan H. M.; Gallo, Richard L.; Mörgelin, Matthias; Nizet, Victor; Naim, Hassan Y.; Köckritz-Blickwede, Maren von

doi:10.1159/000363699

Cited by 114 publications

(121 citation statements)

References 31 publications

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“…We found that purified neutrophil DNA and NETs released by PMA-treated neutrophils, when supplemented with LL-37, were resistant to degradation by S. aureus, S. pneumoniae, and GAS nucleases (21). These results were recapitulated using other cationic AMPs, with the cationicity of the agents correlating with the degree of resistance to degradation.…”

Section: Degradation Of Netsmentioning

confidence: 76%

“…The relevance of NET evasion by pathogens is further supported by evidence that the body also appears to "fight back"-for example, high concentrations of the antimicrobial peptide, LL-37, within NETs increases resistance to the action of DNases (21), and the presence of anti-ACT in the sera of patients infected with B. pertussis indicates the participation of humoral responses in combating the specific pathways by which pathogens modify NETs.…”

Section: Discussionmentioning

confidence: 98%

“…G-actin, a natural pharmacologic inhibitor of type I DNases, has been shown to prevent Sda1-mediated degradation of NETs (10) and certain patients with systemic lupus erythematosus produce specific DNase1 inhibitors that act against endogenous serum DNase1 (44). Other therapeutic opportunities involve protecting NETs from degradationhigh concentrations of LL-37 increase DNA resistance to pathogen DNases (21), and NETs are protected from degradation in systemic lupus erythematosus due to the deposition of autoantibodies, which are thought to shield them from serum DNase1 (44). Furthermore, targetable bacterial regulators of nuclease expression have been described, including period circadian protein homolog 1, which regulates GAS Sda1 expression (45), and the mgrA and Staphylococcal accessory regulator Z transcriptional regulators, which up-regulate S. aureus nuc expression (46).…”

Section: Discussionmentioning

confidence: 99%

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Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens

Storisteanu¹,

Pocock²,

Cowburn

et al. 2017

Am J Respir Cell Mol Biol

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101

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The release of neutrophil extracellular traps (NETs) is a major immune mechanism intended to capture pathogens. These histoneand protease-coated DNA structures are released by neutrophils in response to a variety of stimuli, including respiratory pathogens, and have been identified in the airways of patients with respiratory infection, cystic fibrosis, acute lung injury, primary graft dysfunction, and chronic obstructive pulmonary disease. NET production has been demonstrated in the lungs of mice infected with Staphylococcus aureus, Klebsiella pneumoniae, and Aspergillus fumigatus. Since the discovery of NETs over a decade ago, evidence that "NET evasion" might act as an immune protection strategy among respiratory pathogens, including group A Streptococcus, Bordetella pertussis, and Haemophilus influenzae, has been growing, with the majority of these studies being published in the past 2 years. Evasion strategies fall into three main categories: inhibition of NET release by down-regulating host inflammatory responses; degradation of NETs using pathogen-derived DNases; and resistance to the microbicidal components of NETs, which involves a variety of mechanisms, including encapsulation. Hence, the evasion of NETs appears to be a widespread strategy to allow pathogen proliferation and dissemination, and is currently a topic of intense research interest. This article outlines the evidence supporting the three main strategies of NET evasion-inhibition, degradation, and resistance-with particular reference to common respiratory pathogens.

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Section: Degradation Of Netsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens

Storisteanu¹,

Pocock²,

Cowburn

et al. 2017

Am J Respir Cell Mol Biol

Self Cite

101

View full text Add to dashboard Cite

show abstract

“…Strikingly, S aureus also has a strong ability to evade killing by NETs through release of both a nuclease and adenosine synthase . LL‐37 blocks nuclease activity, thus protecting it from degradation by the nuclease, and LL‐37‐treated NETs are distinctly more resistant to S aureus nuclease degradation than nontreated NETs . Respiratory viral infections are often implicated in CRS exacerbation .…”

Section: Discussionmentioning

confidence: 99%

LL‐37 promotes neutrophil extracellular trap formation in chronic rhinosinusitis with nasal polyps

Cao

Chen

Sun

et al. 2019

Clin Experimental Allergy

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Background Neutrophil accumulation has been observed in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the functions of neutrophils are poorly understood. Neutrophils produce neutrophil extracellular traps (NETs), which are involved in a variety of chronic inflammatory pathologies. LL‐37 is the only member of the cathelicidin family in human. Objective Our aims were to examine the presence of NETs in CRSwNP and to investigate the regulatory effect of LL‐37 on NET formation. Methods Nasal polyp tissues were investigated for the presence of NETs by using immunofluorescent (IF) staining. The expression and distribution of LL‐37 were examined by using quantitative RT‐PCR, ELISA, IF, and immunohistochemistry. Purified peripheral neutrophils were stimulated with LL‐37 and stained with IF to identify NETs. NETs% was defined as percentage of NET‐generating neutrophils to the total number of neutrophils. Results Neutrophil extracellular traps were located in the subepithelial layer of nasal polyps and control tissues. Nasal polyps had higher NETs% compared with that of controls (23.01% ± 3.43% vs 4.52% ± 1.33%, P < 0.0001). NET count was also increased in nasal polyps. NET count correlated with neutrophil count (r = 0.908, P < 0.001). LL‐37 protein and mRNA levels were upregulated in nasal polyps. LL‐37 was distributed in the epithelial and subepithelial layer and mainly expressed by neutrophils. Moreover, LL‐37 promoted peripheral neutrophils to form NETs in a dose‐dependent manner ex vivo. Interestingly, dexamethasone did not inhibit the effect of LL‐37 on inducing NET formation. Furthermore, peripheral neutrophils from CRSwNP patients were more susceptible to LL‐37‐mediated NET formation, compared with neutrophils derived from control subjects. In addition, NETs released LL‐37 in vivo and ex vivo. Conclusion Neutrophil extracellular traps are significantly increased in nasal polyps and LL‐37 induces NET formation in CRSwNP patients. These findings indicate that NETs may contribute to the pathogenesis of neutrophilic inflammation in CRSwNP.

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“…Recently, bactericidal activity of extracellular DNA against Pseudomonas aeruginosa , a common respiratory pathogen in CF, was described [18]. Antimicrobial proteins bound to neutrophil extracellular traps may have several roles, including antimicrobial activity, and they also protect these structures against degradation induced by bacterial nucleases [19]. It is exciting to see that novel roles for extracellular DNA in the airways continue to be unraveled.…”

mentioning

confidence: 99%