Treponema pallidum flagellins stimulate MMP-9 and MMP-13 expression via TLR5 and MAPK/NF-κB signaling pathways in human epidermal keratinocytes

Jiang, Chao; Xu, Man; Kuang, Xingxing; Xiao, Jian; Tan, Manyi; Xie, Yanping; Xiao, Yao; Zhao, Feijun; Wu, Yimou

doi:10.1016/j.yexcr.2017.09.040

Cited by 38 publications

(22 citation statements)

References 36 publications

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“…As a highly evolutionarily conserved PAMP (pathogen-associated molecular pattern), flagellin can be recognized by the cell surface through TLR5 and the cytosolic NOD-like receptor protein 4 (NLRC4) inflammasome receptor NAIP5, which contributes to activation of inflammatory responses and secretion of proinflammatory cytokines and chemokines during bacterial infections 35 , 47 , 48 . The T. pallidum flagellin induced MMP-9 and MMP-13 expression in keratinocytes, which are involved in activation and regulation through the NF-κB and MAPK signaling pathways 22 . These results suggest that the T. pallidum flagellin may be crucial for triggering inflammation, which may contribute to skin inflammatory responses and keratinocyte-mediated ECM degradation during T. pallidum infection.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Lithgow et al reported that animals immunized with Tp0751 displayed attenuated lesion development, inhibition of T. pallidum dissemination and increased cellular infiltration at lesion sites 10 . Our work reported here used a recombinant flagellin to stimulate augmented production of MMPs which are involved in the degradation of various components of the extracellular matrix (ECM) to facilitate cell migration and invasion 22 . Therefore, the qPCR results clearly demonstrate that pcDNA3/FlaB3 is a promising vaccine candidate, because immunization with this protein significantly reduces T. pallidum dissemination within the host.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study showed that T. pallidum flagellins upregulated IL-6 and IL-8 via the TLR5 and MAPK/NF-ƙB signaling pathways in THP-1 cells 21 . In another study, T. pallidum flagellin (FlaB1, FlaB2, or FlaB3) stimulation augmented the production of MMPs (matrix metalloproteinases) in HaCaT cells via the MyD88-dependent TLR5 signaling pathway 22 . Furthermore, the filament core protein FlaB3 is homologous to the N-terminal and C-terminal regions of the flagellins of Salmonella enterica and Escherichia coli 23 , 24 .…”

Section: Introductionmentioning

confidence: 95%

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Immunogenicity and protective efficacy against Treponema pallidum in New Zealand rabbits immunized with plasmid DNA encoding flagellin

Zheng

Xiao

et al. 2018

Emerging Microbes & Infections

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Plasmid DNA encoding flagellin FlaB3 was used as a vaccination candidate for the evaluation of immunogenicity and protection against Treponema pallidum subsp. pallidum dissemination. First, intramuscular injection of the flagellin encoded by the plasmid DNA into New Zealand rabbits elicited both humoral and cellular immune responses. Total IgG production increased in response to flagellin. In addition, serum IFN-γ secretion and CD8+ cells were substantially greater in the rabbits immunized with the plasmid encoding flagellin FlaB3 than those in the rabbits immunized with recombinant flagellin. The flagellin encoded by the plasmid DNA induced significant upregulation of serum IL-6 and IL-8 compared to that of the control rabbits. Subsequently, intradermal challenge of the vaccinated New Zealand rabbits with 1 × 107T. pallidum resulted in a significant reduction of the bacterial organ burden in the blood, liver, spleen, and testicles in the flagellin plasmid DNA-vaccinated rabbits. Furthermore, the histopathological analysis demonstrated that the rabbits immunized with the plasmid DNA-encoded flagellin (FlaB3) showed better immune protection. These findings provide evidence that plasmid DNA-encoded flagellin (FlaB3) may be useful as a potential immunization route for future development of a vaccine to inhibit T. pallidum dissemination in related animals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Immunogenicity and protective efficacy against Treponema pallidum in New Zealand rabbits immunized with plasmid DNA encoding flagellin

Zheng

Xiao

et al. 2018

Emerging Microbes & Infections

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“…These alignments show that the TLR5 binding site region is highly conserved in all leptospiral FlaBs. Therefore each of the four FlaB subunit could potentially signal through TLR5, since leptospiral FlaBs share the 2 first consensus with TLR5 activating bacteria and the different residue observed in the consensus number 3 is also present in TLR5-activating Treponema flagellins ( 44 ).…”

Section: Resultsmentioning

confidence: 99%

Escape of TLR5 Recognition by Leptospira spp.: A Rationale for Atypical Endoflagella

et al. 2020

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Holzapfel et al. TLR5 Evasion by Leptospires the FlaB, but not the FlaA subunits. Altogether, in contrast to different bacteria that modify their flagellin sequences to escape TLR5 recognition, our study suggests that the peculiar central localization and stability of the FlaB monomers in the periplasmic endoflagellae, associated with the downregulation of FlaB subunits in hosts, constitute an efficient strategy of leptospires to escape the TLR5 recognition and the induced immune response.

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“…MAPK1 is an important transmitter of signals from the cell surface to the nucleus in NOD-like receptor signaling pathway. It can activate the release of various inflammatory factors, chemokines, and adhesion factors mediated by NF-KB signaling pathways and aggravate the pathological changes of DN [40]. When inflammatory reaction happens, MAPK1 will promote IL-1, TNF-α, and IL-1β entry into glomerular cells by activating nod-like receptor signaling pathway and increase cell damage.…”

Section: Journal Of Diabetes Researchmentioning

confidence: 99%

Uncovering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Pharmacology

Guo

Dai

Gao

et al. 2020

Journal of Diabetes Research

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Background. Diabetic nephropathy (DN), characterized by hyperglycemia, hypertension, proteinuria, and edema, is a unique microvascular complication of diabetes. Traditional Chinese medicine (TCM) Astragalus membranaceus (AM) has been widely used for DN in China while the pharmacological mechanisms are still unclear. This work is aimed at undertaking a network pharmacology analysis to reveal the mechanism of the effects of AM in DN. Materials and Methods. In this study, chemical constituents of AM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), and the potential targets of AM were identified using the Therapeutic Target Database (TTD). DisGeNET and GeneCards databases were used to collect DN-related target genes. DN-AM common target protein interaction network was established by using the STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to further explore the DN mechanism and therapeutic effect of AM. The network diagrams of the active component-action target and protein-protein interaction (PPI) networks were constructed using Cytoscape software. Results. A total of 16 active ingredients contained and 78 putative identified target genes were screened from AM, of which 42 overlapped with the targets of DN and were considered potential therapeutic targets. The analysis of the network results showed that the AM activity of component quercetin, formononetin, calycosin, 7-O-methylisomucronulatol, and quercetin have a good binding activity with top ten screened targets, such as VEGFA, TNF, IL-6, MAPK, CCL3, NOS3, PTGS2, IL-1β, JUN, and EGFR. GO and KEGG analyses revealed that these targets were associated with inflammatory response, angiogenesis, oxidative stress reaction, rheumatoid arthritis, and other biological process. Conclusions. This study demonstrated the multicomponent, multitarget, and multichannel characteristics of AM, which provided a novel approach for further research of the mechanism of AM in the treatment of DN.

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Treponema pallidum flagellins stimulate MMP-9 and MMP-13 expression via TLR5 and MAPK/NF-κB signaling pathways in human epidermal keratinocytes

Cited by 38 publications

References 36 publications

Immunogenicity and protective efficacy against Treponema pallidum in New Zealand rabbits immunized with plasmid DNA encoding flagellin

Immunogenicity and protective efficacy against Treponema pallidum in New Zealand rabbits immunized with plasmid DNA encoding flagellin

Escape of TLR5 Recognition by Leptospira spp.: A Rationale for Atypical Endoflagella

Uncovering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Pharmacology

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