Involvement of P2X7 receptor in neuronal degeneration triggered by traumatic injury

Nadal-Nicolás, Francisco M.; Galindo‐Romero, Caridad; Valiente‐Soriano, Francisco J.; Barberà-Cremades, María; deTorre-Minguela, Carlos; Salinas‐Navarro, Manuel; Pelegrı́n, Pablo; Agudo‐Barriuso, Marta

doi:10.1038/srep38499

Cited by 23 publications

(24 citation statements)

References 78 publications

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“…The P2X7 receptor is implicated in multiple forms of neural degeneration ( Sanderson et al, 2014 ; Sperlagh and Illes, 2014 ). Neuronal loss after axotomy was reduced in P2X7 knock out mice ( Nadal-Nicolas et al, 2016 ) while the receptor is also implicated in Alzheimer’s disease ( Miras-Portugal et al, 2015 ). Activation of the P2X7 receptor was implicated in a study of traumatic brain injury, with expression of IL-1β reduced in knock out mice ( Kimbler et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain

Albalawi

Beckel

et al. 2017

Front. Cell. Neurosci.

114

109

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Inflammatory responses play a key role in many neural pathologies, with localized signaling from the non-immune cells making critical contributions. The NLRP3 inflammasome is an important component of innate immune signaling and can link neural insult to chronic inflammation. The NLRP3 inflammasome requires two stages to contribute: priming and activation. The priming stage involves upregulation of inflammasome components while the activation stage results in the assembly and activation of the inflammasome complex. The priming step can be rate limiting and can connect insult to chronic inflammation, but our knowledge of the signals that regulate NLRP3 inflammasome priming in sterile inflammation is limited. This study examined the link between mechanical strain and inflammasome priming in neural systems. Transient non-ischemic elevation of intraocular pressure increased mRNA for inflammasome components IL-1β, NLRP3, ASC, and CASP1 in rat and mouse retinas. The elevation was greater 1 day after the insult, with the rise in IL-1β most pronounced. The P2X7 receptor was implicated in the mechanosensitive priming of IL-1β mRNA in vivo, as the antagonist Brilliant Blue G (BBG) blocked the increased expression, the agonist BzATP mimicked the pressure-dependent rise in IL-1β, and the rise was absent in P2X7 knockout mice. In vitro measurements from optic nerve head astrocytes demonstrated an increased expression of IL-1β following stretch or swelling. This increase in IL-1β was eliminated by degradation of extracellular ATP with apyrase, or by the block of pannexin hemichannels with carbenoxolone, probenecid, or 10panx1 peptide. The rise in IL-1β expression was also blocked by P2X7 receptor antagonists BBG, A839977 or A740003. The rise in IL-1β was prevented by blocking transcription factor NFκB with Bay 11-7082, while the swelling-dependent fall in NFκB inhibitor IκB-α was reduced by A839977 and in P2X7 knockout mice. In summary, mechanical trauma to the retina primed NLRP3 inflammasome components, but only if there was ATP release through pannexin hemichannels, and autostimulation of the P2X7 receptor. As the P2X7 receptor can also trigger stage two of inflammasome assembly and activation, the P2X7 receptor may have a central role in linking mechanical strain to neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain

Albalawi

Beckel

et al. 2017

Front. Cell. Neurosci.

114

109

View full text Add to dashboard Cite

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“…Taken together, these studies may point toward a greater vulnerability in the OFF pathway under pathological conditions due to greater P2X7 receptor and pannexin-1 expression or function. While the P2X7 receptor has been implicated in potentiating RGC death following increased IOP 68,69 and ONC, 70 the importance of the P2X7 receptor in different RGC types under pathological conditions remains unassessed.…”

Section: The Pannexin-1 and P2x7 Receptor Complexmentioning

confidence: 99%

Potential mechanisms of retinal ganglion cell type‐specific vulnerability in glaucoma

Wang

Lee

Bui

et al. 2020

Clinical and Experimental Optometry

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Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type‐specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types – particularly OFF RGCs. Several mechanisms may contribute to type‐specific vulnerability, including differences in the expression of calcium‐permeable receptors (for example pannexin‐1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets.

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“…ATP stimulation evokes the release of pro‐inflammatory cytokines IL‐6, TNF‐α, and CCL2 in primary microglia, which was absent when P2X7 was deleted (Morigiwa et al, ; Shieh et al, ). In a murine model of axonal injury that culminates in the death of retinal neurons, P2X7‐deficient mice exhibited a delayed loss of retinal neurons and a decrease in phagocytic microglia (Nadal‐Nicolas et al, ). Moreover, intravitreal administration of the selective P2X7 antagonist A438079 delayed axotomy‐induced ganglion cell death.…”

Section: Targeting Mononuclear Phagocytes In Retinal Degenerative Dismentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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Involvement of P2X7 receptor in neuronal degeneration triggered by traumatic injury

Cited by 23 publications

References 78 publications

The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain

The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain

Potential mechanisms of retinal ganglion cell type‐specific vulnerability in glaucoma

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

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