Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing
Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing
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DOI：
10.1096/fj.15-272450
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发表时间：
2015-09-01
期刊：
影响因子：
4.8
通讯作者：
Hasko, Gyoergy
中科院分区：
文献类型：
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作者：
Csoka, Balazs;Nemeth, Zoltan H.;Hasko, Gyoergy
细胞外的ATP通过P2X7受体(P2X7Rs)结合并传递信号，以炎症依赖和非依赖的方式调节免疫功能。本研究用P2X7(-/-)小鼠、药理激动剂三磷酸腺苷镁盐(mg-ATP；100 mg/kg，EC50约1.32 mM)和苯甲酰-三磷酸腺苷(BZ-ATP；10 mg/kg，EC50约285 mU)和拮抗剂氧化三磷酸腺苷(oxi-ATP；40 mg/kg，IC50约100 mU M)来证明，在盲肠结扎和穿刺术诱导的多菌败血症中，P2X7R的激活对控制小鼠的死亡率、细菌传播和炎症是至关重要的。我们在P2X7(-/-)骨髓嵌合小鼠、腹腔巨噬细胞过继转移和髓系特异性P2X7(-/-)小鼠身上的结果表明，巨噬细胞上的P2X7R信号对于P2X7Rs的保护作用是必不可少的。P2X7R信号通过增强巨噬细胞对细菌的杀灭来保护细菌，巨噬细胞不依赖于炎症体。通过使用连接蛋白(Cx)通道阻断剂Gap27(0.1 mg/kg，IC50约为0.25mM)和Pannexin通道阻滞剂丙磺舒(10 mg/kg，IC50约为11.7mU)，我们发现通过Cx释放ATP对于抑制炎症和细菌负荷是重要的。综上所述，靶向P2X7Rs为利用内源性保护性免疫机制治疗脓毒症提供了新的机会。
Extracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7(-/-) mice, the pharmacological agonists ATP-magnesiumsalt (Mg-ATP; 100 mg/kg, EC50 approximate to 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 approximate to 285 mu M), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 approximate to 100 mu M) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice. Our results with P2X7(-/-) bone marrow chimeric mice, adoptive transfer of peritoneal macrophages, and myeloid-specific P2X7(-/-) mice indicate that P2X7R signaling on macrophages is essential for the protective effect of P2X7Rs. P2X7R signaling protects through enhancing bacterial killing by macrophages, which is independent of the inflammasome. By using the connexin (Cx) channel inhibitor Gap27 (0.1 mg/kg, IC50 approximate to 0.25 mu M) and pannexin channel inhibitor probenecid (10 mg/kg, IC50 approximate to 11.7 mu M), we showed that ATP release through Cx is important for inhibiting inflammation and bacterial burden. In summary, targeting P2X7Rs provides a new opportunity for harnessing an endogenous protective immune mechanism in the treatment of sepsis.