LL-37 Peptide Enhancement of Signal Transduction by Toll-like Receptor 3 Is Regulated by pH

Singh, Divyendu; Vaughan, Robert C.; Kao, C. Cheng

doi:10.1074/jbc.m114.582973

Cited by 43 publications

(49 citation statements)

References 35 publications

(37 reference statements)

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“…However, studies on other endosomal TLRs and their ligands show the potential importance of endosomal degradation of cathelicidins. A recent report on activation of TLR3 by RNA-LL-37 complexes in epithelial cells indicated that interaction between LL-37 and RNA was lost during endosomal acidification (39). Although the stability of LL-37-RNA complexes at low pH are unclear (39,40), proteolytic breakdown could be the reason for the loss of RNA-LL-37 interaction and increased TLR3 activation.…”

Section: Discussionmentioning

confidence: 99%

“…A recent report on activation of TLR3 by RNA-LL-37 complexes in epithelial cells indicated that interaction between LL-37 and RNA was lost during endosomal acidification (39). Although the stability of LL-37-RNA complexes at low pH are unclear (39,40), proteolytic breakdown could be the reason for the loss of RNA-LL-37 interaction and increased TLR3 activation. In addition, increased LPS uptake was detected in epithelial cells in the presence of LL-37 (41).…”

Section: Discussionmentioning

confidence: 99%

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Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Coorens

Dijk

Bikker

et al. 2015

The Journal of Immunology

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Cathelicidins are essential in the protection against invading pathogens through both their direct antimicrobial activity and their immunomodulatory functions. Although cathelicidins are known to modulate activation by several TLR ligands, little is known about their influence on DNA-induced macrophage activation. In this study, we explored the effects of cathelicidins on DNA-induced activation of chicken macrophages and elucidated the intracellular processes underlying these effects. Our results show that chicken cathelicidin (CATH)-2 strongly enhances DNA-induced activation of both chicken and mammalian macrophages because of enhanced endocytosis of DNA–CATH-2 complexes. After endocytosis, DNA is liberated from the complex because of proteolytic breakdown of CATH-2, after which TLR21 is activated. This leads to increased cytokine expression and NO production. Through the interaction with DNA, CATH-2 can play an important role in modulating the immune response at sites of infection. These observations underline the importance of cathelicidins in sensing bacterial products and regulating immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Coorens

Dijk

Bikker

et al. 2015

The Journal of Immunology

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“…At acid pH, LL-37 is monomeric, at physiological pH cathecidin aggregates [37]. In the work of Singh, D. and coauthors (2014), it was found that the enhancement of LL-37 signal transduction by the Toll-like receptor 3 (TLR3) is regulated by pH [38]. Upon acidification by endosomes, the oligomerized LL-37 dissociates into LL-29 (a natural LL-37 fragment lacking the C-terminal part) [39], which is unable to transmit TLR3 signals [38].…”

Section: Resultsmentioning

confidence: 99%

“…In the work of Singh, D. and coauthors (2014), it was found that the enhancement of LL-37 signal transduction by the Toll-like receptor 3 (TLR3) is regulated by pH [38]. Upon acidification by endosomes, the oligomerized LL-37 dissociates into LL-29 (a natural LL-37 fragment lacking the C-terminal part) [39], which is unable to transmit TLR3 signals [38]. In this case, inhibition of cathepsins, which includes proteases, whose activity is activated by endosome acidification, resulted in an increase in the half-life of LL-37 from cells [38].…”

Section: Resultsmentioning

confidence: 99%

Роль Ендогенних Антимікробних Пептидів У Виникненні Пневмонії В Дітей Раннього Віку

Lezhenko¹,

Абатуров²,

Pashkovа³

et al. 2021

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Abstract. The comprehensive examination included 204 children with community-acquired pneumonia aged 2 months to 3 years. It was found that in young children with community-acquired pneumonia, the main etiologic factor is bacteria Streptococcus pneumoniae (36.8 %). The content of endogenous antimicrobial peptides was identified in the serum of 20 young children with pneumonia and in 17 children in the control group. It is proved that the development of pneumonia in young children occurs on the background of the reduction in the blood serum levels of β 1 -defensin and cathelicidin LL-37. The lowest values of LL-37 were identified in children with pneumonia caused by Streptococcus pneumoniae. The analysis of the content of vitamin D metabolites in the serum showed that in children with pneumonia, concentration of 25-hydroxyvitamin D was 1.4 times lower compared with healthy children (р < 0.05). Established deficiency of vitamin D metabolites in young children

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“…The presence of the cathelicidin precursor protein has also been found to facilitate nucleic acid associations with TLR in the endolysosome (43). LL-37 has been shown to bind dsRNA and traffic it to endosomes where it releases the dsRNA in a pH-dependent manner (44). Additionally, structural changes of LL-37⅐ligand complex were shown by electron microscopy illustrating that LL-37 and poly(I:C) individually formed globular structures, but a complex of the two formed filamentous structures (23).…”

Section: Discussionmentioning

confidence: 99%

Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells

Adase

Borkowski

Zhang

et al. 2016

Journal of Biological Chemistry

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A critical function for skin is that when damaged it must simultaneously identify the nature of the injury, repair barrier function, and limit the intrusion of pathogenic organisms. These needs are carried out through the detection of damageassociated molecular patterns (DAMPs) and a response that includes secretion of cytokines, chemokines, growth factors, and antimicrobial peptides (AMPs). In this study, we analyzed how non-coding double-stranded RNA (dsRNAs) act as a DAMP in the skin and how the human cathelicidin AMP LL-37 might influence growth factor production in response to this DAMP. dsRNA alone significantly increased the expression of multiple growth factors in keratinocytes, endothelial cells, and fibroblasts. Furthermore, RNA sequencing transcriptome analysis found that multiple growth factors increase when cells are exposed to both LL-37 and dsRNA, a condition that mimics normal wounding. Quantitative PCR and/or ELISA validated that growth factors expressed by keratinocytes in these conditions included, but were not limited to, basic fibroblast growth factor (FGF2), heparin-binding EGF-like growth factor (HBEGF), vascular endothelial growth factor C (VEGFC), betacellulin (BTC), EGF, epiregulin (EREG), and other members of the transforming growth factor ␤ superfamily. These results identify a novel role for DAMPs and AMPs in the stimulation of repair and highlight the complex interactions involved in the wound environment.

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LL-37 Peptide Enhancement of Signal Transduction by Toll-like Receptor 3 Is Regulated by pH

Cited by 43 publications

References 35 publications

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Роль Ендогенних Антимікробних Пептидів У Виникненні Пневмонії В Дітей Раннього Віку

Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells

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