Lipopolysaccharide Enhances Wnt5a Expression through Toll-like Receptor 4, Myeloid Differentiating Factor 88, Phosphatidylinositol 3-OH Kinase/AKT and Nuclear Factor Kappa B Pathways in Human Dental Pulp Stem Cells

Wang, He; Wang, Zhihua; Zhou, Zeyuan; Zhang, Yaqing; Zhu, Qinglin; Wei, Kewen; Yuan, Lin; Cooper, Paul R.; Smith, Anthony J.; Yu, Qing

doi:10.1016/j.joen.2013.09.011

Cited by 70 publications

(49 citation statements)

References 34 publications

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“…We detected greatly upregulation of NF-κB and IL-1β (at the mRNA and protein level) in spinal cords limited to the ischemic region between 12 and 36 h after I/R injury and was accompanied with a selective increase in TLR 4 expression. Pyrrolidine dithiocarbamate (PDTC) is a low-molecular-weight thiol compound, was initially regarded as a potent inhibitor of NF-κB by inhibiting factor I-κB phosphorylating, thus preventing the dissociation of the NF-κB -IκB complex and interfering with the generation of proinflammatory cytokines [26-28]. It has been reported that intrathecal PDTC can delay and reverse mechanical allodynia in several neuropathic pain conditions [27].…”

Section: Discussionmentioning

confidence: 99%

Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats

Wang

Fang

et al. 2014

Mol Brain

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BackgroundInflammatory reaction in blood–spinal cord barrier (BSCB) plays a crucial role in ischemia/reperfusion (I/R) injury. It has been shown that microglia could be activated through Toll-like receptors (TLRs). Therefore, we hypothesize that TLR4 is involved in the microglial activation and BSCB disruption after I/R.ResultsTo verify our hypothesis, we analyzed the behavioral data, changes of BSCB permeability, as well as expressions of microglial marker Iba-1 and TLR4 in spinal cord I/R model induced by 14 min aortic occlusion. Double immunostaining reveals that after I/R, Iba-1 immunoreactivity increased gradually 12 h after reperfusion and maintained at a such level throughout 36 h. Such increasing pattern of Iba-1 expression is consistent with the increases in Evan’s Blue (EB) extravasation, spinal water content and mechanical allodynia demonstrated by lowed withdrawal threshold to Von Frey filaments. Moreover, double immunostaining suggested that TLR4 was highly expressed in microglia. Intrathecal infusion of minocycline and TAK-242 (TLR4 inhibitor) treatment attenuated I/R-induced allodynia and BSCB leakage. In contrast, LPS induced TLR4 expression aggregated above-mentioned injuries. Furthermore, the nuclear factor-kappa B (NF-κB) activity has a similar profile as TLR4 activity. It is consisted with the results of NF-κB mRNA and protein expression changes and activation of downstream cytokine, IL-1β. Expectedly, intrathecal infusion of pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor, showed similar protective effects as minocycline and TAK-242. In addition, our data show that TLR4 closely involved in I/R-induced inflammatory damage induced neuronal apoptosis. Significantly, neutralizing TLR4 function largely reduced neuronal apoptosis determined by NeuN immunoreactivity in ventral gray matter and increased percentage of double-label cells with cleaved caspase3, whereas LPS reversed these effects. Similarly, inhibitions of microglia and NF-κB with minocycline or PDTC treatment accordingly perform the same protective effects on I/R injury.ConclusionThe results indicate that compromised BSCB caused by I/R injury lead to spinal microglial activation and TLR4, its membrane-bound receptor, up-regulation, which then initiate neuro-inflammation and neuro-apoptosis via NF-κB/ IL-1β pathway. To inhibit the positive feedback loop of TLR4-microglia-NF-κB/ IL-1β pathway by minocycline, TAK-242 (TLR4 inhibitor) and pyrrolidine dithiocarbamate (PDTC, NF-κB inhibitor) may provide new targets for treating I/R injury in clinic.

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Section: Discussionmentioning

confidence: 99%

Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats

Wang

Fang

et al. 2014

Mol Brain

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“…Moreover, WNT5α mRNA and protein expressions rapidly increased in response to LPS treatment in a time-and dose-dependent manner. LPS-induced WNT5α expression is mediated through the TLR4/MyD88/PI3K/ AKT signaling pathways, which subsequently activate NF-κB signaling pathway in hDPSCs [ 103 ].…”

Section: Signaling Pathway Networkmentioning

confidence: 99%

Signaling Pathways in Dental Stem Cells During Their Maintenance and Differentiation

Liu

Zhou

et al. 2016

Stem Cell Biology and Regenerative Medicine

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“…Roshan MH et al found that Wnt5a expression was decreased in atherosclerosis‐associated inflammation following TLR2 and TLR4 knockout, while He X et al showed that the TLR4 pathway up‐regulated Wnt5a in mesenchymal stem cells treated with LPS. Furthermore, He W et al found that Wnt5a also activated NF‐κB in LPS‐stimulated human dental pulp stem cells in a TLR4/MyD88 dependent manner. Taken together, these findings indicate that Wnt5a is involved in TLR4 and LOX‐1 mediated inflammatory response in peri‐implantitis.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a is involved in LOX‐1 and TLR4 induced host inflammatory response in peri‐implantitis

Zhang

Liu

et al. 2019

J of Periodontal Research

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Background and objective Peri‐implantitis is a plaque‐associated pathological condition occurring in tissues around dental implants, characterized by inflammation in the peri‐implant mucosa and subsequent progressive loss of supporting bone. Wnt5a is the activating ligand of the non‐canonical Wnt signaling pathways and plays important roles in leukocyte infiltration and cytokine/ chemokine production in inflammatory disorders. Previous studies showed that Wnt5a was significantly up‐regulated in gingival tissues of chronic and aggressive periodontitis. However, the roles and the regulatory mechanisms of Wnt5a in peri‐implantitis are not well known. Methods The expression of Wnt5a in gingival tissues collected from 8 healthy implant patients and 8 peri‐implantitis patients was analyzed by Western blotting and immunofluorescence. Porphyromonas gingivalis infected macrophages isolated from the peripheral blood of healthy volunteers were used as an in vitro cellular model of peri‐implantitis. Using neutralizing antibodies, inhibitors and siRNA, the production and roles of Wnt5a in peri‐implantitis were assessed by immunofluorescence, quantitative polymerase chain reaction (RT‐PCR) and Western blotting. Unpaired two‐tailed Student's t test was used to compare qRT‐PCR and Western blotting results. P ≤ .05 was considered statistically significant. Results Wnt5a was highly expressed in the gingival tissues of peri‐implantitis patients. Compared to controls, Wnt5a increased in P gingivalis infected macrophages. Wnt5a production in response to P gingivalis infection was dependent on LOX‐1 and TLR4. Compared to controls, Wnt5a knockdown impaired IL‐1β, MCP‐1, and MMP2 production induced by P gingivalis infection. Conclusion Our results indicate that Wnt5a is involved in LOX‐1 and TLR4 induced inflammatory signature via inflammatory cytokines production in response to P gingivalis infection. These findings demonstrate that Wnt5a maybe an important component of the host immune response in peri‐implantitis.

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Lipopolysaccharide Enhances Wnt5a Expression through Toll-like Receptor 4, Myeloid Differentiating Factor 88, Phosphatidylinositol 3-OH Kinase/AKT and Nuclear Factor Kappa B Pathways in Human Dental Pulp Stem Cells

Cited by 70 publications

References 34 publications

Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats

Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats

Signaling Pathways in Dental Stem Cells During Their Maintenance and Differentiation

Wnt5a is involved in LOX‐1 and TLR4 induced host inflammatory response in peri‐implantitis

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