CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury.
CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury.
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CD39限制P2X7受体炎症信号传导并减轻脓毒症诱导的肝损伤
DOI：
10.1016/j.jhep.2017.05.021
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发表时间：
2017-10
影响因子：
25.7
通讯作者：
Coutinho-Silva R
中科院分区：
文献类型：
--
作者：
Savio LEB;de Andrade Mello P;Figliuolo VR;de Avelar Almeida TF;Santana PT;Oliveira SDS;Silva CLM;Feldbrügge L;Csizmadia E;Minshall RD;Longhi MS;Wu Y;Robson SC;Coutinho-Silva R
败血症的严重程度可能与导致肝损伤的过度炎症反应有关。P2 X7受体被细胞外ATP（eATP）激活通过增加细胞因子产生而加剧炎症;而CD 39（ENTPD 1）清除eATP以产生腺苷，从而限制P2 X7激活并导致A2 A受体刺激。我们的目的是确定P2 X7和A2 A受体在控制巨噬细胞反应方面的功能相互作用，从而影响脓毒症和肝损伤的结果。在C57 BL/6野生型（WT）和CD 39 −/−小鼠中通过盲肠结扎和穿孔诱导脓毒症。使用腹膜或骨髓来源的巨噬细胞进行了几项体外测定，以确定CD 39外核苷酸酶活性及其在脓毒症诱导的肝损伤中的作用。巨噬细胞中的CD 39表达限制ATP-P2 X7受体促炎信号传导。P2 X7受体矛盾地增强CD 39活性。抑制和/或缺失LPS致敏的巨噬细胞中的P2 X7受体可减弱细胞因子产生和炎症信号传导，并防止ATP诱导的CD 39活性增加。脓毒症CD 39 −/−小鼠表现出更高水平的炎性细胞因子，并表现出比WT小鼠更明显的肝损伤。药理学P2 X7阻断在很大程度上防止了组织损伤、细胞凋亡、细胞因子产生和脓毒症WT肝脏中炎症信号通路的激活，同时仅减弱了CD 39 −/−小鼠中的这些结果。此外，P2 X7阻断与腺苷A2 A受体刺激的组合完全抑制细胞因子的产生，炎症信号通路的激活，并保护脓毒症CD 39 −/−小鼠免受肝损伤。CD 39通过清除eATP并最终产生腺苷减轻脓毒症相关的肝损伤我们提出，在脓毒症的急性期，CD 39的增强将抑制P2 X7反应并触发腺苷能信号传导，以限制全身炎症并恢复肝脏稳态。
The severity of sepsis can be linked to excessive inflammatory responses resulting in hepatic injury. P2X7 receptor activation by extracellular ATP (eATP) exacerbates inflammation by augmenting cytokine production; while CD39 (ENTPD1) scavenges eATP to generate adenosine, thereby limiting P2X7 activation and resulting in A2A receptor stimulation. We aim to determine the functional interaction of P2X7 and A2A receptors on controlling macrophage response, consequently impacting the outcome of sepsis and liver injury. Sepsis was induced by cecal ligation and puncture in C57BL/6 wild-type (WT) and CD39−/− mice. Several in vitro assays were performed using peritoneal or bone marrow derived macrophages to determine CD39 ectonucleotidase activity and its role in sepsis-induced liver injury. CD39 expression in macrophages limits ATP-P2X7 receptor pro-inflammatory signaling. P2X7 receptor paradoxically boosts CD39 activity. Inhibition and/or deletion of P2X7 receptor in LPS-primed macrophages attenuates cytokine production and inflammatory signaling as well as preventing ATP-induced increases in CD39 activity. Septic CD39−/− mice exhibit higher levels of inflammatory cytokines and show more pronounced liver injury than WT mice. Pharmacological P2X7 blockade largely prevents tissue damage, cell apoptosis, cytokine production, and the activation of inflammatory signaling pathways in the liver from septic WT, while only attenuating these outcomes in CD39−/− mice. Furthermore, the combination of P2X7 blockade with adenosine A2A receptor stimulation completely inhibits cytokine production, the activation of inflammatory signaling pathways, and protects septic CD39−/− mice against liver injury. CD39 attenuates sepsis-associated liver injury by scavenging eATP and ultimately generating adenosine. We propose boosting of CD39 would suppress P2X7 responses and trigger adenosinergic signaling to limit systemic inflammation and restore liver homeostasis during the acute phase of sepsis.
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影响因子：
5.4
作者：
Levesque, Sebastien A.;Kukulski, Filip;Enjyoji, Keiichi;Robson, Simon C.;Sevigny, Jean
通讯作者：
Sevigny, Jean
DOI：
10.1084/jem.20061097
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lappas CM;Day YJ;Marshall MA;Engelhard VH;Linden J
通讯作者：
Linden J
影响因子：
32.4
作者：
Chalmin, Fanny;Mignot, Gregoire;Ghiringhelli, Francois
通讯作者：
Ghiringhelli, Francois
影响因子：
4.8
作者：
Csoka, Balazs;Nemeth, Zoltan H.;Hasko, Gyoergy
通讯作者：
Hasko, Gyoergy
影响因子：
13.5
作者：
Antoniades, Charalambos Gustav;Khamri, Wafa;Thursz, Mark
通讯作者：
Thursz, Mark