P2X7 receptors induce degranulation in human mast cells

Abstract

Mast cells play important roles in host defence against pathogens, as well as being a key effector cell in diseases with an allergic basis such as asthma and an increasing list of other chronic inflammatory conditions. Mast cells initiate immune responses through the release of newly synthesised eicosanoids and the secretion of pre-formed mediators such as histamine which they store in specialised granules. Calcium plays a key role in regulating both the synthesis and secretion of mast-cell-derived mediators, with influx across the membrane, in particular, being necessary for degranulation. This raises the possibility that calcium influx through P2X receptors may lead to antigen-independent secretion of histamine and other granule-derived mediators from human mast cells. Here we show that activation of P2X7 receptors with both ATP and BzATP induces robust calcium rises in human mast cells and triggers their degranulation; both effects are blocked by the P2X7 antagonist AZ11645373, or the removal of calcium from the extracellular medium. Activation of P2X1 receptors with αβmeATP also induces calcium influx in human mast cells, which is significantly reduced by both PPADS and NF 449. P2X1 receptor activation, however, does not trigger degranulation. The results indicate that P2X7 receptors may play a significant role in contributing to the unwanted activation of mast cells in chronic inflammatory conditions where extracellular ATP levels are elevated.Electronic supplementary materialThe online version of this article (doi:10.1007/s11302-016-9497-4) contains supplementary material, which is available to authorized users.

P2Y13 and P2X7 receptors modulate mechanically induced adenosine triphosphate release from mast cells

“…These results support the idea that ATP mobilization during MS occurs at least in part via P2X 7 R activation, along with P2Y 13 R, and added to accumulating evidences of P2X 7 R‐mediated ATP regeneration [23,47,48] . Regarding MCs, P2X 7 R was indicated to contribute to the degranulation of mouse bone marrow‐derived MCs, [46] LAD 2 human MCs line [49] and MCs in the colons of mice [50] …”

Orai and TRPC channel characterization in FcεRI‐mediated calcium signaling and mediator secretion in human mast cells

“…; Wareham et al. ; Wareham and Seward ); therefore, demonstrating that this level of mRNA expression could be sufficient to provide a functional contribution to cell physiology.…”

“…Interestingly, TRPM7 (<0.4) and P2X7 (<2 -data not shown) were detected at similar levels to the TRPC family subtypes. Both these channels have previously been functionally characterized in human mast cells (Wykes et al 2007;Wareham et al 2009;Wareham and Seward 2016); therefore, demonstrating that this level of mRNA expression could be sufficient to provide a functional contribution to cell physiology. In order to verify the consistency of expression of TRPC subtypes in HLMCs between different lung donors, qPCR was performed on four additional lung donors.…”

Non‐IgE mediated mast cell activation

“…286 A recent study also showed that P2X7 is responsible for high concentration of ATP-mediated MC degranulation in LAD2 human MCs. 287 Notably, P2X7 is highly expressed by ex vivo cultured human MCs (HMC-1 and activated CBMC), but no detection of this receptor was found in human primary MCs isolated from lung and skin. 284 ATP levels are significantly elevated in the airways of asthmatic patients after allergen challenge and in mice in a model of ovalbumin (OVA)-induced asthma.…”

“…ATP‐mediated activation of P2X7 induces the production of inflammatory cytokines (IL‐6, TNF‐α, and oncostatin M), chemokines (CCL2, CCL7, and CXCL2), and leukotrienes from MCs, which subsequently exacerbate intestinal inflammation . A recent study also showed that P2X7 is responsible for high concentration of ATP‐mediated MC degranulation in LAD2 human MCs . Notably, P2X7 is highly expressed by ex vivo cultured human MCs (HMC‐1 and activated CBMC), but no detection of this receptor was found in human primary MCs isolated from lung and skin …”