The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain.
The P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain.
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DOI：
10.3389/fncel.2017.00227
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发表时间：
2017
影响因子：
5.3
通讯作者：
Mitchell CH
中科院分区：
文献类型：
--
作者：
Albalawi F;Lu W;Beckel JM;Lim JC;McCaughey SA;Mitchell CH
炎症反应在许多神经病理学中起关键作用，来自非免疫细胞的局部信号传导起关键作用。NLRP 3炎性小体是先天免疫信号传导的重要组成部分，可以将神经损伤与慢性炎症联系起来。NLRP 3炎性体需要两个阶段来贡献：引发和激活。引发阶段涉及炎性体组分的上调，而活化阶段导致炎性体复合物的组装和活化。引发步骤可以是速率限制的，并且可以将损伤与慢性炎症联系起来，但是我们对无菌炎症中调节NLRP 3炎性体引发的信号的了解是有限的。本研究探讨了神经系统中机械应变和炎性小体引发之间的联系。短暂的非缺血性眼内压升高增加了大鼠和小鼠视网膜中炎性体组分IL-1β、NLRP 3、ASC和CASP 1的mRNA。损伤后1天升高更大，其中IL-1β的升高最明显。P2 X7受体参与了体内IL-1β mRNA的机械敏感性引发，因为拮抗剂亮蓝G（BBG）阻断了IL-1β表达的增加，激动剂BzATP模拟了IL-1β的压力依赖性升高，并且在P2 X7敲除小鼠中不存在这种升高。视神经乳头星形胶质细胞的体外测量表明，拉伸或肿胀后IL-1β的表达增加。通过用腺苷三磷酸双磷酸酶降解细胞外ATP，或通过用甘珀酸、丙磺舒或10 panx 1肽阻断泛连接蛋白半通道，IL-1β的这种增加被消除。IL-1β表达的升高也被P2 X7受体拮抗剂BBG、A839977或A740003阻断。通过Bay 11-7082阻断转录因子NFκB可阻止IL-1β的升高，而A839977和P2 X7敲除小鼠中NFκB抑制剂IκB-α的肿胀依赖性下降可减少。总之，对视网膜的机械创伤引发NLRP 3炎性体组分，但仅当存在通过泛连接蛋白半通道的ATP释放和P2 X7受体的自刺激时。由于P2 X7受体也可以触发炎性小体组装和激活的第二阶段，P2 X7受体可能在将机械应变与神经炎症联系起来方面具有核心作用。
Inflammatory responses play a key role in many neural pathologies, with localized signaling from the non-immune cells making critical contributions. The NLRP3 inflammasome is an important component of innate immune signaling and can link neural insult to chronic inflammation. The NLRP3 inflammasome requires two stages to contribute: priming and activation. The priming stage involves upregulation of inflammasome components while the activation stage results in the assembly and activation of the inflammasome complex. The priming step can be rate limiting and can connect insult to chronic inflammation, but our knowledge of the signals that regulate NLRP3 inflammasome priming in sterile inflammation is limited. This study examined the link between mechanical strain and inflammasome priming in neural systems. Transient non-ischemic elevation of intraocular pressure increased mRNA for inflammasome components IL-1β, NLRP3, ASC, and CASP1 in rat and mouse retinas. The elevation was greater 1 day after the insult, with the rise in IL-1β most pronounced. The P2X7 receptor was implicated in the mechanosensitive priming of IL-1β mRNA in vivo, as the antagonist Brilliant Blue G (BBG) blocked the increased expression, the agonist BzATP mimicked the pressure-dependent rise in IL-1β, and the rise was absent in P2X7 knockout mice. In vitro measurements from optic nerve head astrocytes demonstrated an increased expression of IL-1β following stretch or swelling. This increase in IL-1β was eliminated by degradation of extracellular ATP with apyrase, or by the block of pannexin hemichannels with carbenoxolone, probenecid, or 10panx1 peptide. The rise in IL-1β expression was also blocked by P2X7 receptor antagonists BBG, A839977 or A740003. The rise in IL-1β was prevented by blocking transcription factor NFκB with Bay 11-7082, while the swelling-dependent fall in NFκB inhibitor IκB-α was reduced by A839977 and in P2X7 knockout mice. In summary, mechanical trauma to the retina primed NLRP3 inflammasome components, but only if there was ATP release through pannexin hemichannels, and autostimulation of the P2X7 receptor. As the P2X7 receptor can also trigger stage two of inflammasome assembly and activation, the P2X7 receptor may have a central role in linking mechanical strain to neuroinflammation.
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影响因子：
3.4
作者：
Crowston, Jonathan G.;Kong, Yu Xiang G.;Chrysostomou, Vicki
通讯作者：
Chrysostomou, Vicki
影响因子：
7.3
作者：
Donnelly-Roberts, Diana L.;Namovic, Marian T.;Jarvis, Michael F.
通讯作者：
Jarvis, Michael F.
影响因子：
6.2
作者：
Beckel, Jonathan M.;Argall, Arthur J.;Lim, Jason C.;Xia, Jingsheng;Lu, Wennan;Coffey, Erin E.;Macarak, Edward J.;Shahidullah, Mohammed;Delamere, Nicholas A.;Zode, Gulab S.;Sheffield, Val C.;Shestopalov, Valery I.;Laties, Alan M.;Mitchell, Claire H.
通讯作者：
Mitchell, Claire H.
影响因子：
3.3
作者：
Coffey EE;Beckel JM;Laties AM;Mitchell CH
通讯作者：
Mitchell CH
DOI：
10.1085/jgp.201210875
发表时间：
2012-11
期刊：
The Journal of general physiology
影响因子：
--
作者：
Bernier LP
通讯作者：
Bernier LP