Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 108-8639, Japan.
Nat Commun. 2012;3:1034. doi: 10.1038/ncomms2023.
Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors. We find an increase in the numbers of mast cells expressing P2X7 purinoceptors in the colons of mice with colitis and of patients with Crohn's disease. Treatment of mice with a P2X7 purinoceptor-specific antibody inhibits mast cell activation and subsequent intestinal inflammation. Similarly, intestinal inflammation is ameliorated in mast cell-deficient Kit(W-sh/W-sh) mice, and reconstitution with wild-type, but not P2x7(-/-) mast cells results in susceptibility to inflammation. ATP-P2X7 purinoceptor-mediated activation of mast cells not only induces inflammatory cytokines, but also chemokines and leukotrienes, to recruit neutrophils and subsequently exacerbate intestinal inflammation. These findings reveal the role of P2X7 purinoceptor-mediated mast cell activation in both the initiation and exacerbation of intestinal inflammation.
肥大细胞是过敏和炎症性疾病中的效应细胞，但它们在肠道炎症中的确切作用尚不清楚。在这里，我们表明肠道炎症中肥大细胞的激活是由 ATP 反应性 P2X7 嘌呤能受体介导的。我们发现，在结肠炎小鼠和克罗恩病患者的结肠中，表达 P2X7 嘌呤能受体的肥大细胞数量增加。用 P2X7 嘌呤能受体特异性抗体治疗小鼠可抑制肥大细胞激活和随后的肠道炎症。同样，在缺乏肥大细胞的 Kit(W-sh/W-sh) 小鼠中，肠道炎症得到改善，而用野生型而非 P2x7(-/-) 肥大细胞重建则易发生炎症。ATP-P2X7 嘌呤能受体介导的肥大细胞激活不仅诱导炎症细胞因子，还诱导趋化因子和白三烯，招募中性粒细胞，随后加重肠道炎症。这些发现揭示了 P2X7 嘌呤能受体介导的肥大细胞激活在肠道炎症的启动和加重中的作用。
