Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®

Background: Pycnogenol® (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. Aim: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. Findings: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. Conclusions: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).

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Detrimental Role of Heat Shock Protein 60&70 and Toll-like Receptor 4 in Skeletal Muscle Ischaemia In Vitro

Journal of Vascular Surgery ◽

10.1016/j.jvs.2013.02.134 ◽

2013 ◽

Vol 57 (5) ◽

pp. 77S

Author(s):

Ali Navi ◽

Rebekah Yu ◽

Xu Shi-Wen ◽

Sidney Shaw ◽

George Hamilton ◽

...

Keyword(s):

Skeletal Muscle ◽

Heat Shock ◽

Heat Shock Protein ◽

Heat Shock Protein 60 ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Muscle Ischaemia

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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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TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.693342 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yangchun Hu ◽

Chao Li ◽

Xiaojian Wang ◽

Weiwei Chen ◽

Yu Qian ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Neuroprotective Effect ◽

Neurological Dysfunction ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Microglial Polarization ◽

The Relationship

Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of TREM2 and its regulatory mechanism after subarachnoid hemorrhage (SAH). TREM2 siRNA was administered to measure the detrimental role of TREM2 in mediating microglial polarization in vivo and in vitro after experimental SAH. The relationship between Toll-like receptor 4 (TLR4) signaling and TREM2 was further explored. The soluble TREM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that TREM2 mainly located in the microglia and presented a markedly delayed elevation after SAH. TREM2 knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, TLR4 knockout increased the expression of TREM2, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt–Hess grades, obviously enhanced accumulation of soluble TREM2 was detected in the CSF of patients with SAH. TREM2 played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of TREM2 might be potentially suppressed by the hyperactive TLR4 in the early phase of SAH. Pharmacological targeting of TREM2 may be a promising strategy for SAH therapy.

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Regulatory Role of rno-miR-30b-5p in IL-10 and Toll-like Receptor 4 Expressions of T Lymphocytes in Experimental Autoimmune Uveitis In Vitro

Mediators of Inflammation ◽

10.1155/2018/2574067 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Yuanyuan Sun ◽

Dadong Guo ◽

Bin Liu ◽

Xuewei Yin ◽

Huixia Wei ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Protein Levels ◽

Eye Tissues ◽

Spleen And Lymph Nodes ◽

Experimental Autoimmune

Uveitis is a serious eye disease that usually damages young adult’s health. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate messenger RNA (mRNA) expression. It is predicted that rno-miR-30b-5p can regulate the expressions of interleukin-10 (IL-10) and Toll-like receptor 4 (TLR4). In this study, the regulatory role of rno-miR-30b-5p in IL-10 and TLR4 gene expressions was validated using luciferase activity assay. Further, the inflammatory manifestation of the anterior segment and pathological examination of the eye were explored in experimental autoimmune uveitis (EAU) rats. Meanwhile, the levels of rno-miR-30b-5p in eye tissues, spleen, and lymph nodes were measured using quantitative PCR (Q-PCR). IL-10 and TLR4 in spleen and lymph nodes were further separately determined by using Q-PCR and Enzyme-Linked Immunosorbent Assay (ELISA). Moreover, rno-miR-30b-5p mimic and its inhibitor were separately transfected into purified T cells, and the levels of IL-10 and TLR4 were detected using PCR, flow cytometry, and ELISA techniques. Results indicate that rno-miR-30b-5p was downregulated in spleen, lymph nodes, and eye tissues whereas the expressions of IL-10 and TLR4 at mRNA and protein levels were upregulated. The levels of IL-10 and TLR4 were negatively correlated to rno-miR-30b-5p levels. The result of in vitro cell transfection experiment indicates that IL-10 and TLR4 expressions were inhibited at mRNA and protein levels after T cells incubated with rno-miR-30b-5p mimic. However, the IL-10 and TLR4 mRNA levels were upregulated in purified T cells from spleen and lymph nodes after treatment with miR-30b-5p antagonist. In addition, there was no evident change of IL-10 and TLR4 proteins in spleen and lymph node T cells between EAU control and negative treatment groups. Flow cytometry analysis revealed that rno-miR-30b-5p mimic could reduce the number of both IL-10 and TLR4 positive cells, whereas rno-miR-30b-5p inhibitor could increase the number of IL-10 and TLR4 positive cells. Our study demonstrates that rno-miR-30b-5p influences the development of uveitis by regulating the level of IL-10 and TLR4 positive cells, thereby playing a role in the pathogenesis of uveitis.

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Platelet-bound lipopolysaccharide enhances Fc receptor–mediated phagocytosis of IgG-opsonized platelets

Blood ◽

10.1182/blood-2006-12-062695 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4803-4805 ◽

Cited By ~ 91

Author(s):

John W. Semple ◽

Rukhsana Aslam ◽

Michael Kim ◽

Edwin R. Speck ◽

John Freedman

Keyword(s):

Flow Cytometry ◽

Toll Like Receptor ◽

Autoimmune Thrombocytopenia ◽

Toll Like Receptor 4 ◽

Platelet Destruction ◽

Gram Negative ◽

Synergistic Increase

Abstract Platelets express Toll-like receptor 4 (TLR4), and this has been shown to be responsible for the thrombocytopenia induced by lipopolysaccharide (LPS) administration in vivo. We studied the role of LPS in mediating platelet phagocytosis by THP-1 cells in vitro by flow cytometry. Opsonization of platelets with an IgG monoclonal (W6/32) antibody or with IgG autoantibody-positive sera from patients with autoimmune thrombocytopenia (AITP) significantly enhanced platelet phagocytosis (P < .001). In contrast, platelet phagocytosis did not occur if platelets were bound with only LPS. If, however, the LPS-bound platelets were also opsonized with either W6/32 or autoantibody-positive sera with titers greater than 4, there was a significant and synergistic increase in Fc-dependent platelet phagocytosis (P < .001, P = .003, P = .048, and P = .047). These results suggest that, in the presence of antiplatelet antibodies, bacterial products can significantly alter platelet phagocytosis, and this may have relevance to how Gram-negative infections enhance platelet destruction in some patients with AITP.

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