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.

P2X1‐regulated IL‐22 secretion by innate lymphoid cells is required for efficient liver regeneration

“…Thus, modulation of P2X1 has mainly indirect effects by activation of circulating, but not parenchymal, cells. This finding is supported by recent studies that have shown the relevance of P2X1 in other models of inflammation and injury, such as neutrophil migration during endotoxemia . Desensitization is an inherent property of P2X1 receptor and explains decreased secretion of IL‐22 ex vivo and in vivo in the absence of CD39 on liver lymphocytes .…”

P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing Escherichia coli

“…Two recent studies where sepsis-like conditions were induced in ${\text{P}2\text{X}}_1^{-/-}$ mice show contradicting results. One study showed increased survival in ${\text{P}2\text{X}}_1^{-/-}$ mice after LPS injection (10 mg kg −1 ) (Maitre et al, 2015), while another demonstrated decreased survival after injection of 20 mg kg −1 LPS (Lecut et al, 2012) in mice lacking P2X 1 receptors. Since both these studies also had ${\text{P}2\text{X}}_1^{-/-}$ on a C57BL/6 background and thus, a less functioning P2X 7 receptor, this may explain the higher sensitivity in the mice at higher dose of LPS.…”

Endotoxin-induced autocrine ATP signaling inhibits neutrophil chemotaxis through enhancing myosin light chain phosphorylation

“…The P2X1 receptor is also critical for neutrophil sensing of extracellular ATP, but its role in neutrophil migration during inflammation has not been thoroughly characterized. Lecut et al reported that the P2X1 receptor protects against lipopolysaccharide (LPS)-induced mice endotoxemia by dampening neutrophil infiltration and activation (6), whereas Maître et al observed that the P2X1 receptor is required for neutrophil extravasation during LPS-induced mouse endotoxemia (7).…”