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The P2X7 Receptor in Infection and Inflammation
Open accessAbstract
Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.
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In the citing paper
“P2X7, which is widely expressed by immune cells, is the most studied purinergic receptors involved in neurodegeneration.374,375”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [374]
Experimental — accuracy not yet measuredIn the citing paper
“Hyperactivation of P2X7 receptors is closely related to inflammatory processes since they are stimulated by ATP released from distressed cells and induce inflammasome activation [16–18].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“In these circumstances, ATP may act as DAMP, which activates the nuclear transcription factor NF-κB resulting in expression upregulation of pro-IL-1β and pro-IL-18 and the NLRP3 protein [16, 71].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“Consequently, there is an activation of caspase-1 and maturation of IL-1β and IL-18, resulting in pro-inflammatory cytokine release [16, 20, 52, 71, 73].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“The P2X7 receptor is a major activator of the NLRP3 inflammasome in several cell types [16], including macrophages and microglial cells [72, 74–76].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“In fact, the role of P2X7 receptor as a modulator of inflammatory response is well-established [16, 70].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“The massive ATP release following lung mononuclear phagocytes invasion by SARS-CoV-2 can activate P2X7 receptors of antigen-presenting cells and macrophages, increasing cytokine, chemokine and ATP secretion [16].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
In the citing paper
“As discussed by Di Virgilio et al. [106], many processes associated with lung impairment, as seen in COVID-19 patients, are mediated by P2X7 receptors [16].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [16]
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P2X7 receptor in inflammation and pain
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“…and central sensitization, including potassium efflux (Kelley et al., 2019), binding of ATP to purinergic receptors (Silverman et al., 2009; Di Virgilio et al., 2017), TLR activation (Song et al., 2017; Inoue and Tsuda, 2018), as well as either TNF-α or IL-1 β signaling (Yazdi and…”
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“Furthermore, as an agonist of P2X7R, ATP plays an important role in the inflammatory reactions.(10) Therefore, we detected the ATP concentration using ELISA both extracellularly and intracellularly.”
InfluentialInteractions between Macrophages and the Sensory Cells of the Inner EarPreprint
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“Although they are expressed by different cell types, in particular the peripheral immune cells [51, 52] and glial cells, i.e. oligodendrocytes and astrocytes [53, 54], they are mainly expressed by microglia [55], while their expression by neurons is still controversial [56].”
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BackgroundRole and therapeutic targets of P2X7 receptors in neurodegenerative diseases
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Self-citationMetabolic regulation of pathogenic autoimmunity: therapeutic targeting
Teng, X., Cornaby, C., Li, W., & Morel, L. M. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.07.001 · Cited by 38
“Extracellular ATP is released by dying cells to the cytosol and transported into cells by the P2X7 ATP receptor [42].”
BackgroundBidirectional communication between neural and immune systems
Kamimura, D., Tanaka, Y., Hasebe, R., & Murakami, M. (2019) · International Immunology · doi:10.1093/intimm/dxz083 · Cited by 46
Purinergic signaling and tumor microenvironment in cervical Cancer
Pfaffenzeller, M. S., Franciosi, M. L. M., & Cardoso, A. M. (2020) · Purinergic Signalling · doi:10.1007/s11302-020-09693-3 · Cited by 41
“However, the triggering of P2 receptors—as a result of the high levels of extracellular ATP released by abnormal cells present in TME of CeCa—may also initiate adaptive immune responses in other sites [55, 106, 110].”
BackgroundGarré, J. M., Silva, H. M., Lafaille, J. J., & Yang, G. (2020) · Nature Communications · doi:10.1038/s41467-020-15590-5 · Cited by 39
P2 Purinergic Signaling in the Distal Lung in Health and Disease
Wirsching, E., Fauler, M., Fois, G., & Frick, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144973 · Cited by 42
Purinergic signalling in host innate immune defence against intracellular pathogens
Coutinho‐Silva, R., & Savio, L. E. B. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114405 · Cited by 42
Beamer, E. H., Morgan, J. J., Alves, M., Méndez, A. M., Morris, G., Zimmer, B., Conte, G., de Diego-García, L., Alarcón‐Vila, C., Ng, N. K. Y., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15785 · Cited by 39
Novak, I., & Solini, A. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.02.002 · Cited by 38
Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity
Menzel, S., Schwarz, N., Haag, F., & Koch‐Nolte, F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00266 · Cited by 38
Díaz-Pérez, J. A., Killeen, M. E., Yang, Y., Carey, C. D., Falo, L. D., & Mathers, A. R. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.05.018 · Cited by 37
Purinergic signaling in Alzheimer’s disease
Erb, L., Woods, L. T., Khalafalla, M. G., & Weisman, G. A. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.10.014 · Cited by 39
The potential involvement of P2X7 receptor in COVID‐19 pathogenesis: A new therapeutic target?
Pacheco, P. A. F., & Faria, R. X. (2020) · Scandinavian Journal of Immunology · doi:10.1111/sji.12960 · Cited by 37
Diabetes and hypertension: Pivotal involvement of purinergic signaling
Reichert, K. P., Castro, M. F. V., Assmann, C. E., Bottari, N. B., Miron, V. V., Cardoso, A. M., Stefanello, N., Morsch, V. M., & Schetinger, M. R. C. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111273 · Cited by 44
Saber, S., Yahya, G., Gobba, N. A., Sharaf, H., Alshaman, R., Alattar, A., Amin, N. A., El-Shedody, R., Aboutouk, F. H., El-Galeel, Y. A., et al. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s315938 · Cited by 38
P2X7 Receptor Expression in Patients With Serositis Related to Systemic Lupus Erythematosus
Furini, F., Giuliani, A. L., Parlati, M. E., Govoni, M., Di Virgilio, F., & Bortoluzzi, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00435 · Cited by 37
Self-citationZhu, F., Dou, Y., Qin, X. S., Qian, Y., Ma, J., Li, W., Liu, Q., Wang, C., Zhang, Y., Li, Y., et al. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00968-w · Cited by 38
Purinergic receptors in cognitive disturbances
Illés, P., Ulrich, H., Chen, J., & Tang, Y. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106229 · Cited by 38
Kabiljo, J., Laengle, J., & Bergmann, M. M. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-0284-1 · Cited by 36
García-Villalba, J., Hurtado‐Navarro, L., Peñín‐Franch, A., Molina‐López, C., Martínez-Alarcón, L., Angosto-Bazarra, D., Baroja‐Mazo, A., & Pelegrín, P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.894470 · Cited by 37
“The activation of the P2X7 receptor leads to the activation of the NLRP3 inflammasome, the release of the IL-1b and IL-18 cytokines (11, 13), and the shedding of the P2X7 receptor in microparticles (32).”
BackgroundThe NLRP3 Inflammasome in Neurodegenerative Disorders: Insights from Epileptic Models
Palumbo, L., Carinci, M., Guarino, A., Asth, L., Zucchini, S., Missiroli, S., Rimessi, A., Pinton, P., & Giorgi, C. (2023) · Biomedicines · doi:10.3390/biomedicines11102825 · Cited by 39
“In particular, an increased extracellular ATP level leads to the opening of the purinergic P2X7 receptor channels, which ultimately results in K + efflux, making the P2X7 receptor one of the most potent NLRP3 inflammasome activators [68,69].”
BackgroundOpposing effects of the purinergic P2X7 receptor on seizures in neurons and microglia in male mice
Alves, M., Gil, B., Villegas-Salmerón, J., Salari, V., Martins-Ferreira, R., Blázquez, M. A., Méndez, A. M., Gerbatin, R. R., Smith, J., de Diego-García, L., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.05.023 · Cited by 36
“2), in line with P2X7R promoting proinflammatory signaling (Di Virgilio, 2017).”
BackgroundPurinergic P2X7 Receptor: A Cation Channel Sensitive to Tumor Microenvironment
Scarpellino, G., Genova, T., & Munaron, L. (2019) · Recent Patents on Anti-Cancer Drug Discovery · doi:10.2174/1574892814666190116122256 · Cited by 36
The role of microglia and P2X7 receptors in gliomas
Kan, L. K., Williams, D. J., Drummond, K. J., O'Brien, T. J., & Monif, M. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.04.010 · Cited by 37
Role of the P2X7 receptor in in vitro and in vivo glioma tumor growth
Bergamin, L. S., Capece, M., Salaro, E., Sarti, A. C., Falzoni, S., Pereira, M. S. L., Bastiani, M. A. D., Scholl, J. N., Battastini, A. M. O., & Virgilio, F. D. (2019) · Oncotarget · doi:10.18632/oncotarget.27106 · Cited by 36
“The P2X7R might in principle oppose tumor cell proliferation, by virtue of its potent cytotoxic effect when overstimulated, or support tumor progression due to its growth-promoting activity [6, 39].”
BackgroundSelf-citationAlteration of purinergic signaling in diabetes: Focus on vascular function
Zhou, R., Dang, X., Sprague, R. S., Mustafa, S. J., & Zhou, Z. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.02.004 · Cited by 36
The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review
Rossato, M., Vincenzo, A. D., Pagano, C., Hadi, H. E., & Vettor, R. (2020) · Cells · doi:10.3390/cells9041047 · Cited by 36
“The P2X purinergic receptors are ligand-gated cation channels comprising seven different subtypes that have been cloned and characterized and named P2X1-2-3-4-5-6-7 [12].”
BackgroundInfluentialTrageser, K. J., Sebastian-Valverde, M., Naughton, S. X., & Pasinetti, G. M. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00704 · Cited by 36
“The molecular mechanism by which these ion fluxes contribute to the release of pro-inflammatory cytokines are not fully known; however various in vivomodels in which knock-out P2X7 mice were challenged with LPS, demonstrated significantly decreased secretion of IL-1b (28).”
BackgroundLi, N., Geng, C., Hou, S., Fan, H., & Gong, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176303 · Cited by 37
“Transient receptor potential (TRP) channels and P2X receptors are two types of ligand-gated ion channels, which can promote the production of cytokines and chemokines and the activation of NLRP3 inflammasome by recognizing mitochondria-derived reactive oxygen species (ROS) and ATP, respectively, and participate in the…”
Background
Metadata
- Authors
- Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L., & Falzoni, S.
- Affiliations
- University of Ferrara (IT)
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 47
- Issue
- 1
- Pages
- 15-31
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2737555531
- Cited by
- 1,267
- References
- 199
- Citations by year
- 2026: 167 · 2025: 138 · 2024: 164 · 2023: 155 · 2022: 160 · 2021: 161 · 2020: 132 · 2019: 102 · 2018: 78 · 2017: 9
- FWCI
- 9.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, cc-by)
- Funders
- Italian Association for Cancer Research (IG 13025, IG 18581)
- Telethon of Italy (GGP06070)
- ERA-NET Neuron Joint Transnational Project “Nanostroke,” the Ministry of Health of Italy (RF-2011-02348435)
- Italian Ministry of Education, University and Research (RBAP11FXBC_001)
- University of Ferrara
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Keywords
- P2X7 receptor, extracellular ATP, purinergic receptors, NLRP3 inflammasome, inflammation, innate immunity, adaptive immunity, cytokine and chemokine secretion, single nucleotide polymorphisms, cancer, anti-inflammatory therapy, cancer therapy, signal transduction, receptor structure
- MeSH terms
- Animals, Cell Differentiation, Humans, Infections, Inflammation, Macrophages, T-Lymphocytes, Receptors, Purinergic P2X7, Inflammasomes, Purinergic P2X Receptor Agonists
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