Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1Β release through pyrophosphates

Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
The EMBO Journal (Impact Factor: 10.43). 07/2009; 28(14):2114-27. DOI: 10.1038/emboj.2009.163
Source: PubMed


In acute inflammation, extracellular ATP activates P2X(7) ion channel receptors (P2X(7)R) on M1 polarized macrophages to release pro-inflammatory IL-1beta 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-1beta 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-1beta release by other stimuli through two independent mechanisms: inhibition of ROS production and trapping of the inflammasome complex through intracellular clustering of actin filaments.

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Article: Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1Β release through pyrophosphates

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    • "Although M1 and M2 polarisation represents either end of the polarisation scale, it is possible that macrophages can be activated towards a phenotype at any point between these two extremes. Evidence also suggests that macrophages are extremely plastic between activation states, switching rapidly from one to another, and fully reversible upon stimulation with a cytokine that has an opposite effect (Porcheray et al. 2005; Pelegrin and Surprenant 2009). "

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