Figure 8.

Proposed model for inflammasome regulation by extracelluar ATP during macrophage polarization gradient. In M1 polarized macrophages ATP acting through P2X₇R is linked with an increase production of ROS, actin polymerization to the edge of the cell, activation of the NLRP3 inflammasome/caspase-1 and rapid release of the pro-inflammatory mature IL-1β cytokine. However, during the resolving phase of the inflammation M1 macrophages switch their phenotype towards M2 and now P2X₇R uncouples to both ROS production and the NLRP3-inflammasome/caspase-1 pathway although it remains functional in terms of its ion channel activity. Under these conditions (intermediate state 3) the PPi group of ATP acts to further inhibit ROS and induces an intracellular clustering of actin that blocks the inflammasome/activation of caspase-1 and the release of mature IL-1β to enhance the resolving phase of the inflammation. The PPi may result from ATP metabolism by ecto-nucleotidases or may act by phosphate chains remaining attached to the nucleotide molecule.