The P2X1 receptor is required for neutrophil extravasation during lipopolysaccharide-induced lethal endotoxemia in mice.

Abstract

Extracellular ATP is becoming increasingly recognized as an important regulator of inflammation. However, the known repertoire of P2 receptor subtypes responsible for the proinflammatory effects of ATP is sparse. We looked at whether the P2X1 receptor, an ATP-gated cation channel present on platelets, neutrophils, and macrophages, participates in the acute systemic inflammation provoked by LPS. Compared with wild-type (WT) mice, P2X1(-/-) mice displayed strongly diminished pathological responses, with dampened neutrophil accumulation in the lungs, less tissue damage, reduced activation of coagulation, and resistance to LPS-induced death. P2X1 receptor deficiency also was associated with a marked reduction in plasma levels of the main proinflammatory cytokines and chemokines induced by LPS. Interestingly, macrophages and neutrophils isolated from WT and P2X1(-/-) mice produced similar levels of proinflammatory cytokines when stimulated with LPS in vitro. Intravital microscopy revealed a defect in LPS-induced neutrophil emigration from cremaster venules into the tissues of P2X1(-/-) mice. Using adoptive transfer of immunofluorescently labeled neutrophils from WT and P2X1(-/-) mice into WT mice, we demonstrate that the absence of the P2X1 receptor on neutrophils was responsible for this defect. This study reveals a major role for the P2X1 receptor in LPS-induced lethal endotoxemia through its critical involvement in neutrophil emigration from venules.

• Authors: Blandine Maître, Stéphanie Magnenat, Véronique Heim, Catherine Ravanat, Richard J Evans, Henri de la Salle, Christian Gachet, Béatrice Hechler
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 2 Pg. 739-49 (Jan 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25480563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Lipopolysaccharides
• Receptors, Purinergic P2X1

Topics

• Animals
• Blood Coagulation (drug effects, genetics, immunology)
• Endotoxemia (chemically induced, genetics, immunology, pathology)
• Lipopolysaccharides (toxicity)
• Lung (immunology, pathology)
• Macrophages (immunology, pathology)
• Mice
• Mice, Knockout
• Neutrophil Infiltration (drug effects, genetics, immunology)
• Neutrophils (immunology, pathology)
• Receptors, Purinergic P2X1 (genetics, immunology)