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In acute inflammation, extracellular ATP activates P2X 7  ion channel receptors (P2X 7 R) on M1 polarized macrophages to release pro‐inflammatory IL‐1β through activation of the caspase‐1/nucleotide‐binding domain and leucine‐rich repeat receptor containing pyrin domain 3 (NLRP3) inflammasome. In contrast, M2 polarized macrophages are critical to the resolution of inflammation but neither actions of P2X 7 R on these macrophages nor mechanisms by which macrophages switch from pro‐inflammatory to anti‐inflammatory phenotypes are known. Here, we investigated extracellular ATP signalling over a dynamic macrophage polarity gradient from M1 through M2 phenotypes. In macrophages polarized towards, but not at, M2 phenotype, in which intracellular IL‐1β remains high and the inflammasome is intact, P2X 7 R activation selectively uncouples to the NLRP3‐inflammasome activation but not to upstream ion channel activation. In these intermediate M1/M2 polarized macrophages, extracellular ATP now acts through its pyrophosphate chains, independently of other purine receptors, to inhibit IL‐1β release by other stimuli through two independent mechanisms: inhibition of ROS production and trapping of the inflammasome complex through intracellular clustering of actin filaments.

Dynamics of macrophage polarization reveal new mechanism to inhibit IL‐1β release through pyrophosphates