Albalawi Farraj, Lu Wennan, Beckel Jonathan M, Lim Jason C, McCaughey Stuart A, Mitchell Claire H
Department of Anatomy and Cell Biology, University of Pennsylvania, PhiladelphiaPA, United States.
Department of Orthodontics, University of Pennsylvania, PhiladelphiaPA, United States.
Front Cell Neurosci. 2017 Aug 8;11:227. doi: 10.3389/fncel.2017.00227. eCollection 2017.
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 β, and 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 , 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. measurements from optic nerve head astrocytes demonstrated an increased expression of β following stretch or swelling. This increase in β 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 β expression was also blocked by P2X7 receptor antagonists BBG, A839977 or A740003. The rise in β 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.
炎症反应在许多神经病理过程中起关键作用，非免疫细胞的局部信号传导起着至关重要的作用。NLRP3炎性小体是固有免疫信号的重要组成部分，可将神经损伤与慢性炎症联系起来。NLRP3炎性小体发挥作用需要两个阶段：启动和激活。启动阶段涉及炎性小体成分的上调，而激活阶段导致炎性小体复合物的组装和激活。启动步骤可能是限速步骤，并且可以将损伤与慢性炎症联系起来，但我们对无菌性炎症中调节NLRP3炎性小体启动的信号的了解有限。本研究探讨了神经系统中机械应变与炎性小体启动之间的联系。短暂性非缺血性眼压升高可增加大鼠和小鼠视网膜中炎性小体成分β和的mRNA水平。损伤后1天升高更为明显，IL-1β的升高最为显著。P2X7受体与IL-1β mRNA的机械敏感启动有关，因为拮抗剂亮蓝G（BBG）可阻断表达增加，激动剂BzATP模拟了IL-1β的压力依赖性升高，而P2X7基因敲除小鼠中则没有这种升高。对视神经乳头星形胶质细胞的测量表明，拉伸或肿胀后β的表达增加。用腺苷三磷酸双磷酸酶降解细胞外ATP，或用羧苄青霉素、丙磺舒或10panx1肽阻断泛素半通道，可消除β的这种增加。β表达的升高也被P2X7受体拮抗剂BBG、A839977或A740003阻断。用Bay 11-7082阻断转录因子NFκB可阻止β的升高，而A839977和P2X7基因敲除小鼠可降低肿胀依赖性NFκB抑制剂IκB-α的下降。总之，视网膜的机械损伤可启动NLRP3炎性小体成分，但前提是通过泛素半通道释放ATP，并对P2X7受体进行自刺激。由于P2X7受体也可触发炎性小体组装和激活的第二阶段，因此P2X7受体可能在将机械应变与神经炎症联系起来方面起核心作用。
