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The P2X7 Receptor: A Key Player in IL-1 Processing and Release

Davide Ferrari, Cinzia Pizzirani, Elena Adinolfi, Roberto M. Lemoli, Antonio Curti, Marco Idzko, Elisabeth Panther and Francesco Di Virgilio
J Immunol April 1, 2006, 176 (7) 3877-3883; DOI: https://doi.org/10.4049/jimmunol.176.7.3877
Davide Ferrari
*Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
†Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy;
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Cinzia Pizzirani
*Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
†Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy;
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Elena Adinolfi
*Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
†Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy;
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Roberto M. Lemoli
‡Institute of Haematology and Medical Oncology “L. & A. Seragnoli,” University of Bologna, Bologna, Italy; and
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Antonio Curti
‡Institute of Haematology and Medical Oncology “L. & A. Seragnoli,” University of Bologna, Bologna, Italy; and
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Marco Idzko
§Department of Pneumology, University of Freiburg, Freiburg, Germany.
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Elisabeth Panther
§Department of Pneumology, University of Freiburg, Freiburg, Germany.
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Francesco Di Virgilio
*Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
†Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy;
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  • FIGURE 1.
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    FIGURE 1.

    The P2X7R: membrane topology and aa substitutions caused by the main SNPs so far described. The full-length and truncated (ΔC) splice variant of the P2X7R are shown. The truncated form lacks almost the entire COOH tail (249 aa, green, red, and short black traits) but bears an extra 18 aa (light blue trait) due to inclusion of the intron between exons 10 and 11 (94 ). TNFRI homology domain (green) and putative LPS-binding region (red) are shown. Cysteine residues forming putative disulfide bridges are also shown. Amino acid changes are highlighted in yellow boxes, whereas residues involved in ATP binding in exons 2, 3, 8, and 9 are indicated in black.

  • FIGURE 2.
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    FIGURE 2.

    Pathways for P2X7-stimulated IL-1β cleavage and release. Activation of TLRs by LPS causes cytoplasmic accumulation of pro-IL-1β and aggregation of the inflammasome components (step 1). Pro-IL-1β and the inflammasome localize below the inner leaflet of the plasma membrane (step 2). Activation of the P2X7R triggers K+ efflux, which in turn drives loading of some components of the inflammasome (e.g., pro-IL-1β, casp-1, and ASC) into secretory lysosomes (66 ). During this process, procasp-1 is cleaved, and pro-IL-1β is converted into mature IL-1β (step 3). The secretory lysosome content is then secreted via a process requiring P2X7R-dependent K+ efflux, Ca2+ increase, activation of phosphatidylcholine-specific phospholipase C, and both Ca2+-independent phospholipase A2 and Ca2+-dependent phospholipase A2 (step 4). An alternative model hypothesizes that after the inflammasome has aggregated below the inner leaflet of the plasma membrane (step 2), activation of the P2X7R triggers budding of small membrane blebs (microvesicles, notice phosphatidylserine flip in the outer leaflet, red) that trap some of the inflammasome components (e.g., pro-IL-1β, casp-1, and ASC). During this process, which is driven by the K+ loss, procasp-1 is cleaved, and pro-IL-1β is converted into mature IL-1β (step 5). Eventually, plasma membrane blebs pinch off and diffuse into the pericellular space (step 6).

  • FIGURE 3.
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    FIGURE 3.

    Extracellular ATP as a diffusible danger signal generated during bacterial infections. Bacteria enter tissues (step 1) and may directly injure cells and cause ATP release (step 2). Bacterial products (e.g., LPS, step 3) may also cause ATP release (step 4). Extracellular ATP diffuses to activate neighboring cells by paracrine or autocrine pathways (step 4). Macrophages stimulated by LPS and ATP release IL-1-containing microvesicles (step 5). The P2X7R may function as an amplification device to spread the ATP wave as its activation triggers further ATP release (step 6) (75 ).

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The Journal of Immunology: 176 (7)
The Journal of Immunology
Vol. 176, Issue 7
1 Apr 2006
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The P2X7 Receptor: A Key Player in IL-1 Processing and Release
Davide Ferrari, Cinzia Pizzirani, Elena Adinolfi, Roberto M. Lemoli, Antonio Curti, Marco Idzko, Elisabeth Panther, Francesco Di Virgilio
The Journal of Immunology April 1, 2006, 176 (7) 3877-3883; DOI: 10.4049/jimmunol.176.7.3877

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The P2X7 Receptor: A Key Player in IL-1 Processing and Release
Davide Ferrari, Cinzia Pizzirani, Elena Adinolfi, Roberto M. Lemoli, Antonio Curti, Marco Idzko, Elisabeth Panther, Francesco Di Virgilio
The Journal of Immunology April 1, 2006, 176 (7) 3877-3883; DOI: 10.4049/jimmunol.176.7.3877
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