Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation
Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation
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DOI：
10.4049/jimmunol.1900954
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发表时间：
2020-06-15
影响因子：
4.4
通讯作者：
Matsuoka, Isao
中科院分区：
文献类型：
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作者：
Yoshida, Kazuki;Ito, Masa-aki;Matsuoka, Isao
从刺激和/或损伤的细胞释放的细胞外ATP通过刺激各种嘌呤受体来调节生理反应。我们以前表明，ATP增强银诱导的肥大细胞（MC）脱粒通过嘌呤受体类似的离子型P2 X4受体。在这项研究中，我们研究了P2 X4受体在由IgE-Fc γ RI复合物与Ag刺激诱导的MC脱颗粒中的作用，使用从野生型和P2 X4受体缺陷（P2 rx 4（-/-））小鼠制备的骨髓来源的MC（BMMC）。ATP显着增加银诱导的脱颗粒的BMMC制备从野生型小鼠。ATP的这种作用在从P2 rx 4（-/-）小鼠制备的BMMC中降低。通过在P2 rx 4（-/-）BMMCs中表达P2 X4受体，ATP的增强作用得以恢复。P2 X4受体介导的效应即使在分化为结缔组织型MC后也保持不变。P2 X4受体刺激不影响银诱导的钙反应，但增强银诱导的早期信号，如酪氨酸磷酸化的Syk和磷脂酶C-γ。有趣的是，ATP对Syk磷酸化的这些作用不受用Cu 2+（P2 X4受体通道的抑制剂）预处理或去除外部Ca 2+的损害，这表明可能涉及除了通过离子通道活性的Ca 2+内流之外的机制。体内实验表明，全身和皮内被动过敏反应显着减轻P2 rx 4（-/-）小鼠。两者合计，目前的数据表明，P2 X4受体起着至关重要的作用，在ATP诱导的上调MC脱粒的Ag，也有助于在体内的Ag诱导的过敏反应。
Extracellular ATP released from stimulated and/or damaged cells modulates physiological responses via stimulation of various purinoceptors. We previously showed that ATP potentiated the Ag-induced mast cell (MC) degranulation via purinoceptors pharmacologically similar to the ionotropic P2X4 receptor. In this study, we investigated the role of P2X4 receptor in MC degranulation induced by stimulation of IgE-Fc epsilon RI complex with Ag, using bone marrow-derived MCs (BMMCs) prepared from wild type and P2X4 receptor-deficient (P2rx4(-/-)) mice. ATP significantly increased Ag-induced degranulation in BMMCs prepared from wild type mice. This effect of ATP was reduced in BMMCs prepared from P2rx4(-/-) mice. The potentiating effect of ATP was restored by expressing P2X4 receptor in P2rx4(-/-) BMMCs. The P2X4 receptor-mediated effects were maintained even after differentiating into the connective tissue-type MCs. P2X4 receptor stimulation did not affect the Ag-induced Ca2+ response but enhanced Ag-induced early signals, such as tyrosine phosphorylation of Syk and phospholipase C-gamma. Interestingly, these effects of ATP on Syk phosphorylation were not impaired by pretreatment with Cu2+, an inhibitor of the P2X4 receptor channel, or removal of external Ca2+, suggesting that a mechanisms other than Ca2+ influx through ion channel activity may be involved. In vivo experiments revealed that systemic and intradermal passive anaphylaxis responses were significantly alleviated in P2rx4(-/-) mice. Taken together, the present data suggest that the P2X4 receptor plays an essential role in ATP-induced upregulation of MC degranulation in response to Ag, and also contributes to the Ag-induced allergic response in vivo.