Visfatin/eNampt induces endothelial dysfunction in vivo: a role for Toll-Like Receptor 4 and NLRP3 inflammasome

As a traditional Chinese medicine-originated disease-modifying anti-rheumatic drug prescription, Baihu-Guizhi decoction (BHGZD) is extensively used for the treatment of rheumatoid arthritis (RA) with a satisfying therapeutic efficacy. Mechanically, our previous data indicated that BHGZD may ameliorate RA partially by restoring the balance of the “inflammation-immune” system through regulating the TLR4-c-Fos-IL2-TNF-alpha axis. Toll-like receptor 4 (TLR4) has been revealed to be involved in the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome complex. Thus, the aim of the current study was to determine the regulatory effects of BHGZD on the TLR4–mediated inflammasome activation during RA progression based on the modified adjuvant-induced arthritis model (AIA-M) and the lipopolysaccharide/adenosine triphosphate (LPS/ATP)–induced pyroptosis cellular models. As a result, oral administration of BHGZD exhibited prominent improvement in the disease severity of AIA-M rats, such as reducing the redness and swelling of joints, arthritis incidence, arthritic scores, and diameter of the limb and increasing pain thresholds. In line with the in vivo findings, BHGZD treatment effectively inhibited the LPS/ATP–induced pyroptosis of both Raw264.7 macrophage and MH7A cells in vitro by reducing pyroptotic cell death morphology (swollen cells) and decreasing propidium iodide–positive and terminal deoxynucleotidyl transferase–mediated dUTP-fluorescein nick end labeling (TUNEL)–positive cells. Notably, the increased expression levels of TLR4, NLRP3, interleukin 1β, and interleukin 18 proteins and the elevated activities of caspase-1 and lactic dehydrogenase in in vivo and in vitro disease models were markedly reversed by the treatment with BHGZD. In conclusion, the above findings proved the immunomodulatory and anti-inflammatory activities of BHGZD, especially in pyroptosis, which may be attributed to the activation of TLR4–mediated NLRP3 inflammasome signaling.

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Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

Biomedicines ◽

10.3390/biomedicines9060599 ◽

2021 ◽

Vol 9 (6) ◽

pp. 599

Author(s):

Víctor Farré-Alins ◽

Alejandra Palomino-Antolín ◽

Paloma Narros-Fernández ◽

Ana Belen Lopez-Rodriguez ◽

Céline Decouty-Perez ◽

...

Keyword(s):

Injury Severity ◽

White Blood Cells ◽

Serum Amyloid ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Important Link ◽

Tlr4 Mrna ◽

Serum Amyloid A1

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

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Lack of Toll-like receptor 4 decreases lipopolysaccharide-induced bone resorption in C3H/HeJ mice in vivo

Oral Microbiology and Immunology ◽

10.1111/j.1399-302x.2007.00410.x ◽

2008 ◽

Vol 23 (3) ◽

pp. 190-195 ◽

Cited By ~ 29

Author(s):

H. Nakamura ◽

Y. Fukusaki ◽

A. Yoshimura ◽

C. Shiraishi ◽

M. Kishimoto ◽

...

Keyword(s):

Bone Resorption ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Bronchoalveolar Lavage Fluid Utilized Ex Vivo to Validate In Vivo Findings: Inhibition of Gap Junction Activity in Lung Tumor Promotion is Toll-Like Receptor 4-Dependent

Journal of Molecular Biomarkers & Diagnosis ◽

10.4172/2155-9929.1000160 ◽

2013 ◽

Vol 05 (01) ◽

Cited By ~ 2

Author(s):

Ross S Osgood

Keyword(s):

Bronchoalveolar Lavage ◽

Gap Junction ◽

Bronchoalveolar Lavage Fluid ◽

Lung Tumor ◽

Ex Vivo ◽

Tumor Promotion ◽

Lavage Fluid ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Toll-Like Receptor 4 Mutation Protects Obese Mice Against Endothelial Dysfunction by Decreasing NADPH Oxidase Isoforms 1 and 4

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.112.301087 ◽

2013 ◽

Vol 33 (4) ◽

pp. 777-784 ◽

Cited By ~ 75

Author(s):

Chao-Fan Liang ◽

Jacky TC Liu ◽

Yu Wang ◽

Aimin Xu ◽

Paul M. Vanhoutte

Keyword(s):

Endothelial Dysfunction ◽

Nadph Oxidase ◽

Obese Mice ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Ginsenoside Rb1 exerts anti-inflammatory effects in vitro and in vivo by modulating toll-like receptor 4 dimerization and NF-kB/MAPKs signaling pathways

Phytomedicine ◽

10.1016/j.phymed.2020.153197 ◽

2020 ◽

Vol 69 ◽

pp. 153197 ◽

Cited By ~ 5

Author(s):

Hongwei Gao ◽

Naixin Kang ◽

Chao Hu ◽

Ziyu Zhang ◽

Qiongming Xu ◽

...

Keyword(s):

Signaling Pathways ◽

Ginsenoside Rb1 ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Anti Inflammatory

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Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

Infection and Immunity ◽

10.1128/iai.69.4.2025-2030.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2025-2030 ◽

Cited By ~ 32

Author(s):

Shuhua Yang ◽

Shunji Sugawara ◽

Toshihiko Monodane ◽

Masahiro Nishijima ◽

Yoshiyuki Adachi ◽

...

Keyword(s):

Lipid A ◽

Micrococcus Luteus ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Monocytic Cells ◽

Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

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