P2X7 Receptor (P2X7R) of Microglia Mediates Neuroinflammation by Regulating (NOD)-Like Receptor Protein 3 (NLRP3) Inflammasome-Dependent Inflammation After Spinal Cord Injury

Fan, Xiao; Ma, Wei; Zhang, Yingyu; Zhang, Li

doi:10.12659/msm.925491

Cited by 19 publications

(16 citation statements)

References 44 publications

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“…Alternatively, these inhibitory neurotransmitters could also reduce the release of neuronal excitatory neurotransmitters, such as glutamate and ATP, which in turn decrease glial cell activity indirectly ( 44 ). Specifically, it has been demonstrated that P2X purinoceptor 7 (P2X7) and P2X4 are expressed on microglia ( 45 , 46 ). Once these purinergic receptors are activated by ATP, the MAPK pathway (including p38) is phosphorylated, and the downstream pro-inflammatory mediators IL-1β and TNF-α are synthesized and influence neurons to perpetuate the nociceptive response.…”

Section: Discussionmentioning

confidence: 99%

Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia

Wang¹,

Wu²,

Zhang

et al. 2021

Mol Med Rep

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Angina pectoris is cardiac pain that is a common clinical symptom often resulting from myocardial ischemia. Spinal cord stimulation (SCS) is effective in treating refractory angina pectoris, but its underlying mechanisms have not been fully elucidated. The spinal dorsal horn is the first region of the central nervous system that receives nociceptive information; it is also the target of SCS. In the spinal cord, glial (astrocytes and microglia) activation is involved in the initiation and persistence of chronic pain. Thus, the present study investigated the possible cardiac pain-relieving effects of SCS on spinal dorsal horn glia in chronic myocardial ischemia (CMI). CMI was established by left anterior descending artery ligation surgery, which induced significant spontaneous/ongoing cardiac pain behaviors, as measured using the open field test in rats. SCS effectively improved such behaviors as shown by open field and conditioned place preference tests in CMI model rats. SCS suppressed CMI-induced spinal dorsal horn microglial activation, with downregulation of ionized calcium-binding adaptor protein-1 expression. Moreover, SCS inhibited CMI-induced spinal expression of phosphorylated-p38 MAPK, which was specifically colocalized with the spinal dorsal horn microglia rather than astrocytes and neurons. Furthermore, SCS could depress spinal neuroinflammation by suppressing CMI-induced IL-1β and TNF-α release. Intrathecal administration of minocycline, a microglial inhibitor, alleviated the cardiac pain behaviors in CMI model rats. In addition, the injection of fractalkine (microglia-activating factor) partially reversed the SCS-produced analgesic effects on CMI-induced cardiac pain. These results indicated that the therapeutic mechanism of SCS on CMI may occur partially through the inhibition of spinal microglial p38 MAPK pathway activation. The present study identified a novel mechanism underlying the SCS-produced analgesic effects on chronic cardiac pain.

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Section: Discussionmentioning

confidence: 99%

Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia

Wang¹,

Wu²,

Zhang

et al. 2021

Mol Med Rep

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“…Furthermore, there is evidence that neuro-glial communication is affected by upregulation of glial purinergic receptors in neurodegeneration. For instance, microglial upregulated P2X7 (184)(185)(186) leads to an exacerbation of a pro-inflammatory microglial phenotype and increased release of proinflammatory molecules, which disrupt synaptic communication (187)(188)(189). Pro-inflammatory molecules like chemokines or reactive oxygen species also affect oligodendrocytes and astrocytes, causing oligodendrocyte cell death (190)(191)(192) and astrocytic reactivity (6), leading to further cell and network impairment.…”

Section: Purinergic Signaling Crosstalk In Neurodegenerationmentioning

confidence: 99%

Glial Purinergic Signaling in Neurodegeneration

et al. 2021

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Purinergic signaling regulates neuronal and glial cell functions in the healthy CNS. In neurodegenerative diseases, purinergic signaling becomes dysregulated and can affect disease-associated phenotypes of glial cells. In this review, we discuss how cell-specific expression patterns of purinergic signaling components change in neurodegeneration and how dysregulated glial purinergic signaling and crosstalk may contribute to disease pathophysiology, thus bearing promising potential for the development of new therapeutical options for neurodegenerative diseases.

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“…Moreover, the in vivo results demonstrated that CY-09 regressed the xenografted tumor growth of osteosarcoma. The therapeutic value of CY-09 has been mainly reported in inflammatory diseases, including inflammation after spinal cord injuries Fan et al (2020) and cerebral ischemia/reperfusion injuries ( Sun et al, 2020 ). Recently, researchers also focused on contributing chronic inflammation created by NLRP3 activation to carcinogenesis, including proliferation, angiogenesis, immunosuppression, and metastasis Liu et al (2021) , Huang et al (2017) , and Chen et al (2018) showed that blockage of the NLRP3 inflammasome could enhance the antitumor immune responses in head and neck squamous cell carcinoma, suggesting that the NLRP3 inflammasome pathway may be regarded as a novel approach for the treatment of head and neck squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma

et al. 2021

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Despite the development of diagnostic and treatment strategies, the survival outcome of patients with osteosarcoma remains poor. Nod-like receptor protein 3 (NLRP3) plays a crucial role in the inflammasome pathway, which is related to the progression of various tumors. However, the effect of NLRP3 on osteosarcoma has not yet been well explored. Our study aimed to investigate the role of NLRP3 in the malignant biological behavior of osteosarcoma as well as its therapeutic value. Immunohistochemistry was applied to investigate the NLRP3 expression in osteosarcoma and osteochondroma specimens. Cell Counting Kit-8, colony formation, wound healing, transwell, and flow cytometry assays were used to explore the contribution of NLRP3 to the proliferation, migration, invasion, apoptosis and cell cycle distribution of osteosarcoma cells in vitro. Western blot was performed to evaluate the expression of NLRP3 and the related proteins in osteosarcoma cell lines after the blockade of NLRP3 using CY-09 and lentivirus intervention. Furthermore, tumor formation assay was used to analyze the effect of NLRP3 on the growth of osteosarcoma in vivo. The results showed that the NLRP3 protein was overexpressed in osteosarcoma, which was independently correlated with the poor prognosis of patients. Moreover, NLRP3 suppression by the inhibitor of CY-09 or lentivirus-induced gene knockdown inhibited the cell proliferation, migration, invasion and promoted the cell apoptosis and G1 cell cycle arrest in osteosarcoma via targeting the inflammasome pathway. Our in vivo results confirmed that the inhibition of NLRP3 suppressed the tumor formation of osteosarcoma. In conclusion, NLRP3 may be regarded as an independent prognostic biomarker and a potential therapeutic target for osteosarcoma.

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P2X7 Receptor (P2X7R) of Microglia Mediates Neuroinflammation by Regulating (NOD)-Like Receptor Protein 3 (NLRP3) Inflammasome-Dependent Inflammation After Spinal Cord Injury

Cited by 19 publications

References 44 publications

Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia

Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia

Glial Purinergic Signaling in Neurodegeneration

NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma

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