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

EMBO J. 2009 Jul 22;28(14):2114-27. doi: 10.1038/emboj.2009.163. Epub 2009 Jun 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Carrier Proteins / metabolism
  • Cell Polarity*
  • Escherichia coli / immunology
  • Escherichia coli Infections / immunology
  • Inflammation / immunology
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X7


  • Carrier Proteins
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • P2rx7 protein, mouse
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate