Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation

Yoshida, Kazuki; Ito, Masaaki; Sato, Naoko; Obayashi, Kosuke; Yamamoto, Kimiko; Koizumi, Schuichi; Tanaka, Satoshi; Furuta, Kazuyuki; Matsuoka, Isao

doi:10.4049/jimmunol.1900954

Cited by 28 publications

(34 citation statements)

References 40 publications

(60 reference statements)

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“…To answer this question in the P2X4 ko mice, one would need to compare P2X7 expression on innate immune cells from the different P2X4-deficient strains. Interestingly, P2rx7 mRNA expression level in BMMCs from the P2rx4 tm1Ando strain (Yamamoto et al, 2005) where comparable to those of B6 WT BMMCs (Yoshida et al, 2020).…”

Section: Discussionmentioning

confidence: 74%

AP2rx7passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

Er-Lukowiak

Duan

Rassendren

et al. 2020

Preprint

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Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 (B6) background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several 129-originating transgenic mice in which P2rx7-neighboring genes were targeted carry a P2rx7 passenger mutation that affects the vitality and function of T cells. By the example of P2rx4 tm1Rass we demonstrate that CD4 + and CD8 + T cells derived from these mice express higher levels of P2X7 when compared to corresponding cell populations in B6-WT mice. The increased T cell sensitivity towards the P2X7 activators adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD + ) rendered these cells more vulnerable towards NAD-induced cell death (NICD) compared to their B6-WT counterparts. The enhanced NICD sensitivity significantly affected the outcome of functional assays e.g. cytokine production and cell migration. For P2rx4 tm1Rass , we demonstrate that the expression of P2X7 is diminished in several innate immune cell populations, possibly as a side effect of P2rx4 targeting, and independent of the P2rx7 passenger mutation. These results need to be considered when working with P2rx4 tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes and might have implications for other mouse models.

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Section: Discussionmentioning

confidence: 74%

AP2rx7passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

Er-Lukowiak

Duan

Rassendren

et al. 2020

Preprint

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“…Previously, we demonstrated that P2X4R stimulation promotes Ag-induced tyrosine phosphorylation signaling, providing a possible mechanism for synergistic MC degranulation in response to Ag and ATP [13]. However, this mechanism was not involved in the effect of ATP and PGE 2 on MC degranulation, since the response to ATP and PGE 2 was insensitive to the tyrosine kinase inhibitor PP2 or Syk inhibitor R406, both of which inhibited the synergistic degranulation induced by Ag and ATP.…”

Section: Discussionmentioning

confidence: 98%

“…In this study, degranulation induced by ATP and PGE 2 was inhibited by the non-selective PI3K inhibitor LY294002 and PI3Kγ selective inhibitor AS605240; however, ATP did not enhance PGE 2 -induced Akt phosphorylation but rather decreased it slightly. Although ATP itself slightly stimulates Akt phosphorylation, this effect is unchanged in P2X4R KO mice [13], suggesting that ATP-induced Akt phosphorylation is mediated by a receptor other than P2X4R and that P2X4R stimulation does not affect Gβγ-mediated PI3Kγ activation. These results suggest that PI3Kγ activation is necessary for ATP and PGE 2 -induced degranulation but that the downstream mechanism differs to that described for the combination of Ag and PGE 2 [9,11].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to Gi-coupled receptor agonists, we recently reported that extracellular ATP also enhances the Ag-induced degranulation response in bone marrow-derived MCs (BMMCs) by activating the P2X4 receptor (P2X4R), a ligand-gated ion channel [12]. Unlike Gi-coupled receptor agonists, P2X4R stimulation does not induce the PI3K signaling pathway, but enhances the Ag-induced tyrosine phosphorylation of signaling molecules including Syk and phospholipase C (PLC) γ [13]. Based on these results, we hypothesized that stimulation of MCs with ATP and Gi-coupled receptor agonists may cause MC degranulation in an IgE-independent manner.…”

Section: Introductionmentioning

confidence: 99%

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Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine Mast Cells

Yoshida

Tajima

Nagano

et al. 2019

IJMS

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Mast cells (MCs) recognize antigens (Ag) via IgE-bound high affinity IgE receptors (FcεRI) and trigger type I allergic reactions. FcεRI-mediated MC activation is regulated by various G protein-coupled receptor (GPCR) agonists. We recently reported that ionotropic P2X4 receptor (P2X4R) stimulation enhanced FcεRI-mediated degranulation. Since MCs are involved in Ag-independent hypersensitivity, we investigated whether co-stimulation with ATP and GPCR agonists in the absence of Ag affects MC degranulation. Prostaglandin E 2 (PGE 2 ) induced synergistic degranulation when bone marrow-derived MCs (BMMCs) were co-stimulated with ATP, while pharmacological analyses revealed that the effects of PGE 2 and ATP were mediated by EP3 and P2X4R, respectively. Consistently, this response was absent in BMMCs prepared from P2X4R-deficient mice. The effects of ATP and PGE 2 were reduced by PI3 kinase inhibitors but were insensitive to tyrosine kinase inhibitors which suppressed the enhanced degranulation induced by Ag and ATP. MC-dependent PGE 2 -triggered vascular hyperpermeability was abrogated in a P2X4R-deficient mouse ear edema model. Collectively, our results suggest that P2X4R signaling enhances EP3R-mediated MC activation via a different mechanism to that involved in enhancing Ag-induced responses. Moreover, the cooperative effects of the common inflammatory mediators ATP and PGE 2 on MCs may be involved in Ag-independent hypersensitivity in vivo. MC degranulation [6]. For instance, it has been shown that PGE 2 , which is known to mediate inflammation [7], and adenosine, which accumulates extracellularly under ischemic conditions [8], enhance Ag-mediated MC degranulation [9][10][11]. The effects of PGE 2 and adenosine are mediated by the EP3 receptor (EP3R) and A 3 receptor (A 3 R), respectively, and are commonly transmitted via the pertussis toxin (PTX)-sensitive Gi protein, suggesting a similar underlying mechanism. Indeed, several studies have demonstrated that enhancing Ag-induced MC degranulation by co-stimulation with Gi-coupled receptor agonists requires the activation of phosphoinositide 3-kinase (PI3K) γ, a PI3K subclass regulated by the Gi protein βγ subunit [10,11]. These enhanced responses are thought to be involved in exacerbating allergic reactions.In addition to Gi-coupled receptor agonists, we recently reported that extracellular ATP also enhances the Ag-induced degranulation response in bone marrow-derived MCs (BMMCs) by activating the P2X4 receptor (P2X4R), a ligand-gated ion channel [12]. Unlike Gi-coupled receptor agonists, P2X4R stimulation does not induce the PI3K signaling pathway, but enhances the Ag-induced tyrosine phosphorylation of signaling molecules including Syk and phospholipase C (PLC) γ [13]. Based on these results, we hypothesized that stimulation of MCs with ATP and Gi-coupled receptor agonists may cause MC degranulation in an IgE-independent manner. Indeed, we previously showed that co-stimulating BMMCs with ATP and adenosine induced synergistic degranulation via A 3 R [12].With respect...

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“…It was demonstrated that ATP and BzATP (a P2X agonist) increased calcium in human MCs and induced MC degranulation by activating P2X7 receptors [140][141][142]. The P2X4 receptor plays an essential role in ATP-induced upregulation of MC degranulation in response to Ag, and also promotes the Ag-induced systemic and intradermal passive anaphylaxis responses in vivo [143]. Moreover, activation of the P2X4 receptor (P2X4R) is involved in the synergistic effect of prostaglandin (PG) E2 and ATP on murine MC degranulation [144].…”

Section: Adenosine Triphosphate Regulation Of Mast Cellsmentioning

confidence: 99%

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review

Shi

et al. 2020

J Neuroinflammation

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The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell–related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell–related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell–related pathogenesis.

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Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation

Cited by 28 publications

References 40 publications

AP2rx7passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

AP2rx7passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine Mast Cells

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review

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