Treponema pallidum flagellin FlaA2 induces IL-6 secretion in THP-1 cells via the Toll-like receptor 2 signaling pathway

Xie, Yanping; Xu, Man; Xiao, Yao; Liu, Zhuoran; Jiang, Chao; Kuang, Xingxing; Wang, Chuan; Wu, Haiying; Peng, Jizong; Li, Chun; Wang, Yu; Liu, Huaming; Liu, Bin; Zhang, Xiaotuan; Zhao, Feijun; Zeng, Tiebing; Liu, Shuangquan; Wu, Yimou

doi:10.1016/j.molimm.2016.11.005

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…Contrary to studies that suggest that flagellin may be an exogenous substance that triggers inflammation (34)(35)(36), increasing evidence indicates that flagellins play a protective role in inflammation and intestinal barrier functions (9,10,37,38). For example, Salmonella typhimurium-derived flagellin can induce the secretion of anti-inflammatory factors, such as IL-22, from dendritic cells to protect intestinal epithelial barrier (9).…”

Section: Discussionmentioning

confidence: 99%

Roseburia�intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis

Pan

Luo

et al. 2020

Mol Med Rep

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Ulcerative colitis (UC) is a type of inflammatory bowel disease (iBd), which is a chronic, relapsing condition associated with the disorder of gut microbial communities. a previous study reported that levels of Roseburia intestinalis (R.I), a butyrate-producing bacterium, are significantly decreased in patients with IBD and exert an anti-inflammatory function in dextran sulfate sodium (DSS)-induced colitis. However, the role of R.I flagellin in UC and its underlying molecular mechanism are not yet fully understood. Therefore, a DSS-induced colitis model in C57Bl/6 mice and the lPS/ATP-induced THP-1 macrophages were treated with R.I flagellin, which were used to investigate the anti-inflammatory effects of R.I flagellin. The results demonstrated that R.I flagellin decreased colitis-associated disease activity index, colonic shortening and the pathological damage of the colon tissues in murine colitis models. Furthermore, R.I flagellin decreased the serum levels of proinflammatory cytokines and inhibited activation of the nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3) inflammasome in murine colitis. R.I flagellin was also demonstrated to decrease the Gasdermin D to yield the N-terminal fragment membrane pore and inhibit inflammasome-triggered pyroptosis. In vitro analysis indicated that microRNA (miR)-223-3p was involved in the regulation of R.I flagellin on NLRP3 inflammasome activation. Taken together, the results of the present study demonstrated that R.I flagellin inhibited activation of the NLRP3 inflammasome and pyroptosis via miR-223-3p/NLRP3 signaling in macrophages, suggesting that R.I flagellin may be used as a novel probiotic product for the treatment of UC.

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Section: Discussionmentioning

confidence: 99%

Roseburia�intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis

Pan

Luo

et al. 2020

Mol Med Rep

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“…Our data demonstrated that intact PF play a key role in the TLR2-mediated activation of innate immune responses, revealing a novel activity of T. denticola PF. Other motile spirochetes such as Treponema pallidum and Borrelia burgdorferi also undergo PRR engagement primarily through TLR2 (45,46), and the Treponema pallidum flagellar protein FlaA2 induces IL-6 production in human monocytes through TLR2 (47). Interestingly, Porphyromonas gingivalis fimbriae engage TLR2 in human monocytes, resulting in the induction of TNF-␣, IL-6, and IL-8 (48).…”

Section: Figmentioning

confidence: 99%

“…T. denticola PF are composed of three core proteins consisting of homologous flagellin subunits FlaB1, -B2, and -B3 and a distinct FlaA sheath protein (38). Other than their involvement in motility and maintaining cell morphology (28), PF have a limited role in spirochete pathogenesis (47). A recent study demonstrated the glycosylation of T. denticola FlgB proteins in the domain that binds to TLR5 (49).…”

Section: Figmentioning

confidence: 99%

Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

et al. 2018

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is an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated that stimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible for activation of the innate immune system are currently not well defined. In this study, we investigated the role played by periplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-type stimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-type and the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positive strain restored the activation. These findings suggest that stimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.

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“…Toll-like receptor 2 (TLR2), an important member of the TLR family, recognizes bacterial lipoproteins and plays a crucial role in the host defense against bacterial infections, including those caused by T. pallidum [24]. Previous studies showed that TLR2 expressed on endothelial cells mediates the initiation of inflammatory signaling cascades [25].…”

Section: Resultsmentioning

confidence: 99%

Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

Zhang

Yang

Wang

2018

Preprint

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24Chemerin, a chemoattractant protein, is involved in endothelial dysfunction and 25 vascular inflammation in pathological conditions. In a recent study, we observed the 26 upregulation of chemerin in endothelial cells following in vitro treatment with T. 27 pallidum. Here, we investigated the role of chemerin in endothelial cells dysfunction 28 induced by the T. pallidum predicted membrane protein Tp0965. Following 29 stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, 30 chemerin and its ChemR23 receptor were up-regulated, companied with elevated 31 expression of TLR2. Furthermore, chemerin from HUVECs activated endothelial cells 32 via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by 33 upregulated expression of ICAM-1, E-selectin and MMP-2. Activation of endothelial 34 cells depended on the MAPK signaling pathway. In addition, Tp0965-induced 35 chemerin promoted monocytes migration to endothelial cells, also via 36 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 37 in monocytes migration in response to chemerin/ChemR23. Our results highlight the 38 role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to 39 the immunopathogenesis of vascular inflammation of syphilis.40 Author summary 41 Treponema pallidum is the spirochete of syphilis, which causes a chronic system 42 inflammation. Endothelium damage caused by this bacterium is the key step in the 43 systemic dissemination and pathophysiology of syphilis, particularly cardiovascular 44 syphilis and neurosyphilis. In this study, we show a novel molecular mechanism of 3 45 endothelium damage induce by Treponema pallidum predicted membrane protein 46 Tp0965. Chemerin is a recently identified adipocytokine and chemoattractant protein 47 with a crucial role in endothelial dysfunction and vascular inflammation in pathological 48 conditions. Our data show that Tp0965 up-regulated the expression of chemerin and its 49 ChemR23 receptor by endothelial cells in vitro. Furthermore, chemerin from HUVECs 50 activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine 51 manner and depended on the MAPK signaling pathway. In addition, Tp0965-induced 52 chemerin promoted monocytes migration to endothelial cells, also via 53 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 54 in monocytes migration in response to chemerin/ChemR23. These findings contribute 55 to the immunopathogenesis of vascular inflammation of syphilis. 56 57 Introduction 58 Treponema pallidum subsp. pallidum (T. pallidum) is the spirochete of syphilis, a 59 sexually transmitted infection that remains an important public health problem around 60 the world [1]. Infection by this bacterium causes a chronic system inflammation, and if 61 untreated can seriously and irreversibly damage the nervous and cardiovascular system.62 Cardiovascular syphilis is associated with multiple clinical syndromes, of which aortic 63 aneurysms, aortic insufficiency,...

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Treponema pallidum flagellin FlaA2 induces IL-6 secretion in THP-1 cells via the Toll-like receptor 2 signaling pathway

Cited by 19 publications

References 37 publications

Roseburia�intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis

Roseburia�intestinalis‑derived flagellin ameliorates colitis by targeting miR‑223‑3p‑mediated activation of NLRP3 inflammasome and pyroptosis

Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

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