ATP-Gated P2X7 Receptors Require Chloride Channels To Promote Inflammation in Human Macrophages
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Immune cells of myeloid origin show robust expression of ATP-gated P2X7 receptors, two-transmembrane ion channels permeable to Na+, K+, and Ca2+. Receptor activation promotes inflammasome activation and release of the proinflammatory cytokines IL-1β and IL-18. In this study, we show that ATP generates facilitating cationic currents in monocyte-derived human macrophages and permeabilizes the plasma membrane to polyatomic cationic dyes. We find that antagonists of PLA2 and Cl− channels abolish P2X7 receptor–mediated current facilitation, membrane permeabilization, blebbing, phospholipid scrambling, inflammasome activation, and IL-1β release. Our data demonstrate significant differences in the actions of ATP in murine and human macrophages and suggest that PLA2 and Cl− channels mediate innate immunity downstream of P2X7 receptors in human macrophages.
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The P2X7 receptor is widely expressed through the body, including in immune, lung, and CNS cells, mainly microglia and oligodendrocytes.
“The P2X7 receptor is widely expressed through the body [47], including in immune [48], lung [49], and CNS cells, mainly microglia and oligodendrocytes [50–52], whereas its expression in neurons and astrocytes is still under discussion [50, 51, 53–60].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [48]
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- Authors
- Janks, L., Sprague, R. S., & Egan, T. M.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Egan, Terrance M
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-02-01
- Volume
- 202
- Issue
- 3
- Pages
- 883-898
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC6352910
- OpenAlex
- W2906877570
- Cited by
- 45
- References
- 110
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 11 · 2019: 3
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Saint Louis University
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM112188)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- P2X7 receptor, ATP, human macrophages, chloride channels, phospholipase A2, inflammasome activation, IL-1β, IL-18, membrane permeabilization, phospholipid scrambling, cationic current, innate immunity, monocyte-derived macrophages
- MeSH terms
- Adenosine Triphosphate, Adult, Aged, Animals, Cell Line, Cells, Cultured, Female, Humans, Immunity, Innate, Inflammation, Macrophages, Male, Middle Aged, Signal Transduction, Cytokines, Chloride Channels, Mice, Phospholipases A2, Young Adult, Receptors, Purinergic P2X1, Receptors, Purinergic P2X7, Receptors, Purinergic P2X4, Phospholipase A2 Inhibitors
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