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首页> 外文期刊>Infection and immunity >Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release
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Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release

机译：类似Toll受体触发的钙动员可通过细胞外ATP释放保护小鼠免受细菌感染

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Extracellular ATP (eATP), released as a “danger signal” by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in both Escherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only by N-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.
机译：细胞外ATP（eATP）作为受损或受压细胞的“危险信号”释放，在免疫反应的调节中起着重要作用，但是ATP释放与先天免疫反应之间的关系仍然不确定。在这项研究中，我们证明，ATP会通过Toll样受体（TLR）相关信号在大肠杆菌感染的小鼠和脂多糖（LPS）或Pam3CSK4处理的巨噬细胞中释放。仅由N-乙基马来酰亚胺（NEM）才能完全阻止此ATP释放，而不能由羧苄酮（CBX），氟苯那酸（FFA）或丙磺舒来完全阻断ATP的释放，表明胞吐作用在此过程中起关键作用。此外，通过使用U73122，咖啡因和毒胡萝卜素（TG）抑制钙动员，还可大幅降低LPS诱导的ATP释放。此外，ATP以时间和剂量依赖性方式显着增强了白介素-1β（IL-1β）和CCL-2的分泌。同时，ATP刺激也显着促进了巨噬细胞介导的细菌吞噬作用。此外，细胞外ATP通过激活嘌呤能受体减少了入侵细菌的数量并保护了小鼠免受腹膜炎的侵害。从机理上讲，ATP在抗菌免疫反应中明显增加了AKT和ERK的磷酸化。因此，如果我们通过使用苏拉明和吡ido醛磷酸盐-6-偶氮（苯-2,4-二磺酸），四钠盐（PPADS）来阻断P2X和P2Y相关的信号传导途径，则ATP增强的免疫反应将受到明显抑制。 。综上所述，我们的发现揭示了先天性免疫反应中危险信号与TLR信号之间的内在联系，这表明钙动员介导的ATP释放在传染病中具有潜在的治疗意义。

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