Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors
Open Access
- 1 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 3 (1), 1034
- https://doi.org/10.1038/ncomms2023
Abstract
Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors. We find an increase in the numbers of mast cells expressing P2X7 purinoceptors in the colons of mice with colitis and of patients with Crohn's disease. Treatment of mice with a P2X7 purinoceptor-specific antibody inhibits mast cell activation and subsequent intestinal inflammation. Similarly, intestinal inflammation is ameliorated in mast cell-deficient KitW-sh/W-sh mice, and reconstitution with wild-type, but not P2x7−/− mast cells results in susceptibility to inflammation. ATP-P2X7 purinoceptor-mediated activation of mast cells not only induces inflammatory cytokines, but also chemokines and leukotrienes, to recruit neutrophils and subsequently exacerbate intestinal inflammation. These findings reveal the role of P2X7 purinoceptor-mediated mast cell activation in both the initiation and exacerbation of intestinal inflammation.Keywords
This publication has 55 references indexed in Scilit:
- Cre-Mediated Cell Ablation Contests Mast Cell Contribution in Models of Antibody- and T Cell-Mediated AutoimmunityImmunity, 2011
- Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophilsNature Immunology, 2011
- Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritisProceedings of the National Academy of Sciences of the United States of America, 2010
- Inflammatory Bowel DiseaseThe New England Journal of Medicine, 2009
- CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel diseaseProceedings of the National Academy of Sciences of the United States of America, 2009
- A Functional P2X7 Splice Variant with an Alternative Transmembrane Domain 1 Escapes Gene Inactivation in P2X7 Knock-out MiceJournal of Biological Chemistry, 2009
- ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine wayProceedings of the National Academy of Sciences of the United States of America, 2008
- Sphingosine 1-phosphate dependence in the regulation of lymphocyte trafficking to the gut epitheliumThe Journal of Experimental Medicine, 2007
- Chemically induced mouse models of intestinal inflammationNature Protocols, 2007
- Pannexin 1 in erythrocytes: Function without a gapProceedings of the National Academy of Sciences of the United States of America, 2006