A synthetic peptide derived from the D1 domain of flagellin induced the expression of proinflammatory cytokines in fish macrophages

González-Stegmaier, Roxana; Guzmán, Fanny; Alberício, Fernando; Villarroel‐Espíndola, Franz; Romero, Alex; Mulero, Víctoriano; Mercado, Luís

doi:10.1016/j.fsi.2015.09.016

Cited by 12 publications

(6 citation statements)

References 23 publications

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“…The only synthetic small molecule agonists for TLR5 are flagellin derived peptides . These peptides share homology to flagellin’s highly conserved D1 binding domain and can be as small as 13 residues in size.…”

Section: Conjugation Strategiesmentioning

confidence: 99%

“…The only synthetic small molecule agonists for TLR5 are flagellin derived peptides. 129 These peptides share homology to flagellin's highly conserved D1 binding domain and can be as small as 13 residues in size. To the best of our knowledge, conjugates of flagellin derived peptides have yet to be synthesized for vaccine applications.…”

Section: ■ Tlr Agonist Conjugatesmentioning

confidence: 99%

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Toll-like Receptor Agonist Conjugation: A Chemical Perspective

et al. 2018

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Toll-like receptors (TLRs) are vital elements of the mammalian immune system that function by recognizing pathogen-associated molecular patterns (PAMPs), bridging innate and adaptive immunity. They have become a prominent therapeutic target for the treatment of infectious diseases, cancer, and allergies, with many TLR agonists currently in clinical trials or approved as immunostimulants. Numerous studies have shown that conjugation of TLR agonists to other molecules can beneficially influence their potency, toxicity, pharmacokinetics, or function. The functional properties of TLR agonist conjugates, however, are highly dependent on the ligation strategy employed. Here, we review the chemical structural requirements for effective functional TLR agonist conjugation. In addition, we provide similar analysis for those that have yet to be conjugated. Moreover, we discuss applications of covalent TLR agonist conjugation and their implications for clinical use.

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Section: Conjugation Strategiesmentioning

confidence: 99%

Section: ■ Tlr Agonist Conjugatesmentioning

confidence: 99%

Toll-like Receptor Agonist Conjugation: A Chemical Perspective

et al. 2018

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“…This was consistent with the results of previous researchers. 21,40,55 Moreover, F I G U R E 4 Mutant flagellins containing only ND1 domains bind to human TLR5. (A-C) Co-immunoprecipitation was performed to assess the binding of the mutated proteins to human TLR5.…”

Section: Discussionmentioning

confidence: 99%

The N‐terminal D1 domain of Treponema pallidum flagellin binding to TLR5 is required but not sufficient in activation of TLR5

Xie

Tan

et al. 2019

J Cellular Molecular Medi

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Syphilis is a chronic bacterial infection caused by Treponema pallidum (T pallidum) and the pathogenesis that T pallidum infection induces immunopathological damages in skin and other tissues remains unclear. We have previously reported that recombinant flagellins of T pallidum can elicit IL‐6 and IL‐8 transcriptions via TLR5 pathway. To identify the domains which induced the pro‐inflammatory activity and the importance of the interactions between TLR5 and domains, homology‐based modelling and comparative structural analyses revealed that Tpflagellins can combine with TLR5 directly. Deletion mutations showed that the ND1 domain binding to TLR5 is required but not sufficient in TLR5 activation. Moreover, site‐directed mutagenesis analysis indicated that the arginine residue (Tpflagellins R89) of the ND1 domain and its adjacent residues (Tpflagellins L93 and E113) constitute a hot spot that elicits IL‐6, IL‐8 transcriptions and TLR5 activation, and affects the binding of Tpflagellins to TLR5. Taken together, these results give insight into the pathogenesis of T pallidum and may contribute to the future design of Tpflagellins‐based therapeutics and syphilis vaccine.

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“…Inflammatory cytokines, such as IL-1β, IL-10, and TNF-α, are part of the pro- or anti-inflammation immune response [ 36 , 37 , 38 ]. In human primary monocyte-derived macrophages, nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) P3 inflammasome activation is inhibited by PGE2, which is mediated through EP4 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of E-Type Prostanoid Receptor 4 (EP4) from Ayu (Plecoglossus altivelis) and Its Functional Analysis in the Monocytes/Macrophages

Rong

Chen

2016

PLoS ONE

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Prostaglandin E2 (PGE2) plays an important role in a broad spectrum of physiological and pathological processes by interacting with E-type prostanoid receptors (EPs). EP4 is one of four EP subtypes known to mediate the immune response in mammalian monocytes/macrophages. However, the precise function and characteristics of EP4 in fish remain unclear. In this study, we characterized a novel EP4-like (PaEP4L) gene from ayu, Plecoglossus altivelis. The cDNA sequence of PaEP4L is 2781 nucleotides (nts) in length, encoding a polypeptide of 459 amino acid residues with a calculated molecular weight of 51.17 kDa. Sequence comparison and phylogenetic tree analysis showed that PaEP4L shared 76% amino acid identity with that of the Atlantic salmon (Salmo salar). PaEP4L mRNA was detected by real-time quantitative PCR (QPCR) in all tested tissues and head kidney-derived monocytes/macrophages (MO/MФ). It varied greatly in liver, spleen and MO/MФ upon Vibrio anguillarum infection. Western blot analysis revealed a significant increase of PaEP4L in cell homogenates from ayu MO/MФ upon V. anguillarum infection. Moreover, anti-PaEP4L IgG reversed the down-regulation of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) mRNA expression as well as phagocytosis in ayu MO/MФ caused by PGE2. There were no significant differences in the respiratory burst response between PGE2 treated and untreated cells. We further found that cAMP mediated PGE2/PaEP4L signal in ayu MO/MФ. In conclusion, our results indicate that PaEP4L mediates PGE2 effects on ayu MO/MФ function, revealing that EP4 also plays a role in the modulation of cells of the fish’s innate immune system.

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A synthetic peptide derived from the D1 domain of flagellin induced the expression of proinflammatory cytokines in fish macrophages

Cited by 12 publications

References 23 publications

Toll-like Receptor Agonist Conjugation: A Chemical Perspective

Toll-like Receptor Agonist Conjugation: A Chemical Perspective

The N‐terminal D1 domain of Treponema pallidum flagellin binding to TLR5 is required but not sufficient in activation of TLR5

Molecular Characterization of E-Type Prostanoid Receptor 4 (EP4) from Ayu (Plecoglossus altivelis) and Its Functional Analysis in the Monocytes/Macrophages

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