Toll-like receptor-4/p38 MAPK signaling in the dorsal horn contributes to P2X4 receptor activation and BDNF over-secretion in cancer induced bone pain

Meng, Xiaowen; Gao, Jianling; Zuo, Jian; Wang, Lina; Liu, Si-lan; Jin, Xiaohong; Yao, Ming; Namaka, Michael

doi:10.1016/j.neures.2017.06.006

Cited by 28 publications

(10 citation statements)

References 33 publications

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“…However, the addition of p38 shRNA, although eliminated p38 over-activation, ameliorated the expressions of IL-6 and MCP-1 and preserved EVT invasion, without affecting TLR4 expression. Prior studies illustrated that p38 represented a key biological downstream target of TLR4 in both acute/chronic inflammatory disease and cancers (Li et al, 2014; Meng et al, 2017). Nevertheless, different from those studies, we provided evidence that TLR4/p38 pathway was activated during placentation and contributed to insufficient EVT invasion by triggering the release of downstream inflammatory cytokines in exposure to LPS.…”

Section: Discussionmentioning

confidence: 99%

LPS Induces Preeclampsia-Like Phenotype in Rats and HTR8/SVneo Cells Dysfunction Through TLR4/p38 MAPK Pathway

Fan

Gao

et al. 2019

Front. Physiol.

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Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1.

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Section: Discussionmentioning

confidence: 99%

LPS Induces Preeclampsia-Like Phenotype in Rats and HTR8/SVneo Cells Dysfunction Through TLR4/p38 MAPK Pathway

Fan

Gao

et al. 2019

Front. Physiol.

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“…Moreover, the P2X7R/p38/IL-18 pathway was shown to maintain bone cancer pain (Yang et al, 2015). In addition, P2X4, P2Y12, and TLR4 also play an activate role in microglial activation and bone cancer pain (Liu et al, 2017; Mao-Ying et al, 2012; Meng et al, 2017). Microglia produce proinflammatory cytokines such as TNF, IL-1b, and IL-18 to elicit central sensitization and facilitate cancer pain (Liu et al, 2017; Mao-Ying et al, 2012; Yang et al, 2015).…”

Section: Do Microglia Play a Role In Other Pathological Pain Conditions?mentioning

confidence: 99%

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

Chen

Zhang

Qadri

et al. 2018

Neuron

555

459

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The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins and maresins. We also discuss a possible role of microglia in chronic itch.

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“…We conclude that in PD, ATP binds to P2X4R on the surface of microglia, and then activates microglial downstream signaling pathways to produce cytokines and other interleukin factors, such as IL-6 (Meng et al, 2017 ). The released cytokines then bind to their respective receptors on the microglial surface to further accelerate the activation of microglia (Hide et al, 2000 ; Sanz and Di Virgilio, 2000 ; Long-Smith et al, 2010 ; Chertoff et al, 2011 ; McCoy et al, 2011 ; Verderio and Matteoli, 2011 ).…”

Section: Discussionmentioning

confidence: 91%

P2X4R Overexpression Upregulates Interleukin-6 and Exacerbates 6-OHDA-Induced Dopaminergic Degeneration in a Rat Model of PD

Gao

Niu

et al. 2020

Front. Aging Neurosci.

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The pathogenesis of Parkinson’s disease (PD) remains elusive. Current thinking suggests that the activation of microglia and the subsequent release of inflammatory factors, including interleukin-6 (IL-6), are involved in the pathogenesis of PD. P2X4 receptor (P2X4R) is a member of the P2X superfamily of ion channels activated by ATP. To study the possible effect of the ATP-P2X4R signal axis on IL-6 in PD, lentivirus carrying the P2X4R-overexpression gene or empty vector was injected into the substantia nigra (SN) of rats, followed by treatment of 6-hydroxydopamine (6-OHDA) or saline 1 week later. The research found the relative expression of P2X4R in the 6-OHDA-induced PD rat models was notably higher than that in the normal. And P2X4R overexpression could upregulate the expression of IL-6, reduce the amount of dopaminergic (DA) neurons in the SN of PD rats, suggesting that P2X4R may mediate the production of IL-6 to damage DA neurons in the SN. Our data revealed the important role of P2X4R in modulating IL-6, which leads to neuroinflammation involved in PD pathogenesis.

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Toll-like receptor-4/p38 MAPK signaling in the dorsal horn contributes to P2X4 receptor activation and BDNF over-secretion in cancer induced bone pain

Cited by 28 publications

References 33 publications

LPS Induces Preeclampsia-Like Phenotype in Rats and HTR8/SVneo Cells Dysfunction Through TLR4/p38 MAPK Pathway

LPS Induces Preeclampsia-Like Phenotype in Rats and HTR8/SVneo Cells Dysfunction Through TLR4/p38 MAPK Pathway

Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain

P2X4R Overexpression Upregulates Interleukin-6 and Exacerbates 6-OHDA-Induced Dopaminergic Degeneration in a Rat Model of PD

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