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Polarized Cytokine Release Triggered by P2X7 Receptor from Retinal Pigmented Epithelial Cells Dependent on Calcium Influx

Shao, Xiaolei and Guha, Sonia and Lu, Wennan and Campagno, Keith E. and Beckel, Jonathan M. and Mills, Jason A. and Yang, Wenli and Mitchell, Claire H. (2020) Polarized Cytokine Release Triggered by P2X7 Receptor from Retinal Pigmented Epithelial Cells Dependent on Calcium Influx. Cells, 9 (12). p. 2537. ISSN 2073-4409

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Cytokine release from non-inflammatory cells is a key step in innate immunity, and agonists triggering cytokine release are central in coordinating responses. P2X7 receptor (P2X7R) stimulation by extracellular ATP is best known to active the NLRP3 inflammasome and release IL-1β, but stimulation also leads to release of other cytokines. As cytokine signaling by retinal pigmented epithelial (RPE) cells is implicated in retinal neurodegeneration, the role of P2X7R in release of cytokine IL-6 from RPE cells was investigated. P2X7R stimulation triggered IL-6 release from primary mouse RPE, human iPS-RPE and human ARPE-19 cells. IL-6 release was polarized, with predominant rise across apical membranes. IL-6 release was inhibited by P2X7R antagonists A438079, A839977, and AZ10606120, but not the NRTI lamivudine (3TC), P2X1R antagonist NF279, or P2Y1R antagonist MRS2179. P2X7R-mediated IL-6 release required extracellular Ca2+ and was blocked by Ca2+ chelator BAPTA. IL-6 release and Ca2+ elevation occurred rapidly, consistent with vesicular IL-6 staining in unstimulated cells. P2X7R stimulation did not trigger IL-1β release in these unprimed cells. P2X7R-mediated IL-6 release was enhanced in RPE cells from the ABCA4−/− mouse model of retinal degeneration. In summary, P2X7R stimulation triggers rapid Ca2+-dependent IL-6 release across the apical membrane of RPE cells


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Shao, Xiaolei
Guha, Sonia
Lu, Wennan
Campagno, Keith E.
Beckel, Jonathan M.jmbeckel@pitt.edujmbeckel
Mills, Jason A.
Yang, Wenli
Mitchell, Claire H.
Date: 24 November 2020
Date Type: Publication
Journal or Publication Title: Cells
Volume: 9
Number: 12
Publisher: MDPI AG
Page Range: p. 2537
DOI or Unique Handle: 10.3390/cells9122537
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Uncontrolled Keywords: P2X7, retina, IL-6, IL-1β, cytokine release, innate immunity
ISSN: 2073-4409
Official URL:
Funders: The Jody Sack Fund, Research to Prevent Blindness Unrestricted Grant Funds to Scheie Eye Institute, F.M. Kirby Foundation, The Paul and Evanina Bell Mackall Foundation Trust, The Center for Advanced Retinal and Ocular Therapeutics, The Foundation for Fighting Blindness, Penn Institute for Regenerative Medicine
Article Type: Research Article
Date Deposited: 28 Jun 2021 19:10
Last Modified: 28 Jun 2021 19:10


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