Publication: Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1beta release through pyrophosphates
Authors
Pelegrin, Pablo ; Surprenant, Annmarie
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Publisher
EMBO Press
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DOI
10.1038/emboj.2009.163
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info:eu-repo/semantics/article
Description
©2009. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This document is the Accepted version of a Published Work that appeared in final form in The EMBO Journal. To access the final edited and published work see https://doi.org/10.1038/emboj.2009.163
Abstract
In acute inflammation extracellular ATP activates P2X7 ion channel receptors (P2X7R) on M1 polarized macrophages to release pro-inflammatory IL-1bvia 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 P2X7R on these macrophages, nor mechanisms by which macrophages switch from pro-inflammatory to anti-inflammatory phenotypes, are known. Here we investigated extracellular ATP signaling over a dynamic macrophage polarity gradient from M1 through M2 phenotypes. In macrophages polarized towards, but not at, M2 phenotype, where intracellular IL-1b remains high and the inflammasome is intact, P2X7R 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 via its pyrophosphate chains, independently of other purine receptors, to inhibit IL-1b release by other stimuli via two independent mechanisms: inhibition of ROS production and trapping of the inflammasome complex via intracellular clustering of actin filaments.
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Citation
EMBO Journal, volumen 28, nº 14, año 2009, páginas 2114-2127.
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