Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers

Caseley, Emily A.; Muench, Stephen P.; Roger, Sébastien; Mao, Hongju; Baldwin, Stephen A.; Jiang, Lin‐Hua

doi:10.3390/ijms150813344

Cited by 47 publications

(34 citation statements)

References 135 publications

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“…Given the role NLRP3 has in activating IL-1β, it is tempting to suggest that priming of NLRP3, increased NLRP3 activity, and its production of IL-1β may yield similar psychological susceptibilities. Polymorphisms in proteins involved in the upstream regulation of the NLRP3 inflammasome and IL-1β secretion such as indoleamine-pyrrole 2,3-dioxygenase (Cutler et al, 2012) (IDO) and the membrane bound receptor P2X7 (Caseley et al, 2014) also generate a susceptibility to develop psychiatric disorders. As previously described in Section 3.3, the P2X7 protein recognizes extracellular ATP and when bound to it initiates signaling cascades that activates the NLRP3 inflammasome and inflammation.…”

Section: Inflammasomes: At the Nexus Between Inflammation And Psychiamentioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

100

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The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

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Section: Inflammasomes: At the Nexus Between Inflammation And Psychiamentioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

100

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“…In the presence of inflammation or stress, there is a fast increase of extracellular ATP to near millimolar levels quickly mediating stimulation of pro-inflammatory pathways [74]. Some P2X7 receptor polymorphisms appear to protect against infection, but others increase the risk of developing chronic inflammatory diseases [75].…”

Section: Inflammation and P2x Receptorsmentioning

confidence: 99%

P2X ion channel receptors and inflammation

Burnstock

2016

Purinergic Signalling

183

153

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Neuroinflammation limits tissue damage in response to pathogens or injury and promotes repair. There are two stages of inflammation, initiation and resolution. P2X receptors are gaining attention in relation to immunology and inflammation. The P2X7 receptor in particular appears to be an essential immunomodulatory receptor, although P2X1 and P2X4 receptors also appear to be involved. ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses. The purinergic involvement in inflammation is being explored for the development of novel therapeutic strategies.

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“…Further, we theorized that functional variants of the P2RX7 gene encoding amino acid substitutions might relate to the degree of inflammatory response to bacterial challenge. Such variants have been reported in association with other inflammatory disorders, such as rheumatoid arthritis and Crohn's disease . Two approaches were taken to examine this theory, using peripheral blood samples from LAP and healthy subjects: first, testing for genetic association of LAP with specific P2RX7 genotypes and second, testing for correlation between the genetic data and in vitro whole‐blood inflammatory LPS response levels in this cohort.…”

Section: Introductionmentioning

confidence: 99%

Association of P2RX7 functional variants with localized aggressive periodontitis

Harris

Wallace

Huang

et al. 2019

J of Periodontal Research

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Objective The purpose of this study was to investigate involvement of the P2X7 receptor in the rare condition, localized aggressive periodontitis. Material and methods Peripheral blood from 220 African Americans (103 with localized aggressive periodontitis and 117 healthy unrelated controls) was stimulated with lipopolysaccharide from E coli and Porphyromonas gingivalis. P2RX7 single nucleotide polymorphisms rs208294 (H155Y), rs1718119 (T348A), rs2230911 (T357S) and rs3751143 (E496A) were genotyped in 103 localized aggressive periodontitis patients and 117 healthy unrelated subjects. We examined genetic association between four P2RX7 single nucleotide polymorphisms and localized aggressive periodontitis, and tested for correlations between the single nucleotide polymorphisms and inflammatory response to lipopolysaccharide in blood samples from these patients. Results A significant association with localized aggressive periodontitis was observed with rs1718119 A (Thr) allele (P = 0.0063, odds ratio = 1.904) and with a haplotype containing this allele (P = 0.0075). Additionally, significant correlations with these data were found: the rs1718119 G allele correlated with greater production of IL‐6, IL‐2 and GM‐CSF; the C (His) allele of rs208294 correlated with lower levels of IL‐12p40; and the C (Thr) allele of rs2230911 correlated with greater levels of G‐CSF. Conclusion The data from these analyses support a possible biological relationship between P2RX7 genetic variants and inflammatory response in localized aggressive periodontitis patients.

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Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers

Cited by 47 publications

References 135 publications

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

P2X ion channel receptors and inflammation

Association of P2RX7 functional variants with localized aggressive periodontitis

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