ATP-Gated P2X7 Receptors Require Chloride Channels To Promote Inflammation in Human Macrophages

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.