Altered Cytokine Production in Mice Lacking P2X7Receptors*

By Michael Solle, J. Labasi, D. Perregaux, E. Stam, N. Petrushova, B. Koller, R. Griffiths, C. Gabel. Journal of Biological Chemistry, 2001

1,013 citations recorded by the source corpus.

The P2X7 receptor (P2X7R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1β post-translational processing, we have generated a P2X7R-deficient mouse line.P2X7R −/− macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1β comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1β produced by theP2X7R −/− cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1β fromP2X7R −/− macrophages. In response to in vivo lipopolysaccharide injection, both wild-type andP2X7R −/− animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATP-treated, LPS-primedP2X7R −/− animals. Absence of the P2X7R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency,in vivo cytokine signaling cascades are impaired in P2X7R-deficient animals. Together these results demonstrate that P2X7R activation can provide a signal that leads to maturation and release of IL-1β and initiation of a cytokine cascade.

Subfields: Physiology, Public Health, Environmental and Occupational Health, Speech and Hearing

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Citations in the corpus

• Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation (2013, background): “The cell surface receptor P2RX7 has been implicated in Nlrp3 inflammasome activation in response to extracellular ATP (Solle et al., 2001).”
• Caspase‐1‐dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages (2006, background): “In addition, cytolytic pores are observed concurrently with caspase-1 activation in response to extracellular ATP and potassium efflux by lipopolysaccharideactivated macrophages (Steinberg et al., 1987; Solle et al., 2001; Kahlenberg and Dubyak, 2004).”
• Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages1 (2007, background): “Consistent with previous reports (22, 31, 49), we observed that macrophages from P2X7R-null mice exhibited no caspase-1 activation or IL-1 secretion when stimulated with 5 mM ATP, a concentration that will maximally activate P2X7R as well as P2Y1 and P2Y2 receptors (Fig.”
• Mechanisms of Action of Adjuvants (2013, background): “Extracellular ATP triggered stimulation of purinergic P2X7 receptor, resulting in activation of cation channel for K+ efflux and opening of pannexin-1 pore for entry of danger signals generated by alum, activate NLRP3 and subsequently caspase-1 (Solle et al., 2001; Petrilli et al., 2007).”
• Molecular physiology of P2X receptors. (2002, background): “of ATP in macrophages from P2X7 receptor knock-out mice (427).”
• The P2X7 Receptor in Infection and Inflammation (2017, positive): “Investigation of pathophysiological functions of the P2X7R has benefited from the generation of three P2X7R-deficient mouse lines according to different gene disruption strategies (Solle et al., 2001; Sim et al., 2004; Bartlett et al., 2014).”
• Ion Channels in Innate and Adaptive Immunity (2015, background): “P2RX7 P2RX7 is a particularly attractive target to treat autoimmune and inflammatory diseases, given that its inhibition should suppress simultaneously the activation of multiple innate and adaptive immune cells.”
• Critical role for calcium mobilization in activation of the NLRP3 inflammasome (2012, background): “Inhibition of Ca2+ flux was strongest with 2-APB and weaker with XeC and U73122, suggesting that other Ca2+-releasing second messengers or ER Ca2+ release mechanisms may be triggered by P2X7R.”
• Understanding the mechanism of IL-1β secretion (2011, background): “Extracellular ATP acting via the P2X7 receptor induces caspase-1-dependent release of IL-1b [18,19], and is dependent upon the formation of the NLRP3 inflammasome [20].”
• Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain (2005, background): “Uniquely, activation of the P2X7 receptor is also associated with release of mature, biologically active interleukin-1b (IL-1b; Perregaux and Gabel, 1994; Solle et al., 2001), a potent inflammatory cytokine whose downstream effects include induction of nitric oxide synthase (iNOS), cyclooxygenase 2 ”