Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke
Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke
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DOI：
10.1007/s12035-017-0394-9
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发表时间：
2018-02-01
影响因子：
5.1
通讯作者：
Arumugam, Thiruma V.
中科院分区：
文献类型：
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作者：
Fann, David Yang-Wei;Lim, Yun-An;Arumugam, Thiruma V.
多蛋白复合物，称为“炎性小体”，已知会导致缺血性卒中后神经元细胞死亡和脑损伤。缺血性卒中增加了神经元中核苷酸结合寡聚化结构域（NOD）样受体（NLR）含1和3（NLRP 1和NLRP 3）炎性体蛋白的Pyrin结构域以及白细胞介素（IL）-1 β和IL-18的表达和活化。在这项研究中，我们提供的证据表明，NF-κ B和MAPK信号通路的激活是部分负责诱导NLRP 1和NLRP 3炎性体蛋白的表达和激活，这些影响可以减弱使用这两个途径的药理学抑制剂在体外和体内缺血条件下的神经元和脑组织，分别。此外，这些发现提供了支持性证据，即在体外和体内缺血条件下，用静脉内免疫球蛋白（IVIg）制剂治疗可以减少NF-κ B和MAPK信号传导途径的激活，导致NLRP 1和NLRP 3炎性体的表达和激活减少，以及抗凋亡蛋白Bcl-2和Bcl-xL在原代皮层神经元和/或脑组织中的表达增加。总之，这些结果提供了令人信服的证据，即NF-κ B和MAPK信号通路在缺血条件下调节原代皮层神经元和脑组织中NLRP 1和NLRP 3炎性体的表达和活化中起关键作用。此外，用IVIg制剂处理降低了NF-κ B和MAPK信号通路的活化，从而减弱了缺血条件下原代皮层神经元中NLRP 1和NLRP 3炎性体的表达和活化。因此，这些研究结果表明，靶向神经元中炎性小体激活的治疗干预可能为缺血性卒中的未来治疗提供新的机会。
Multi-protein complexes, termed "inflammasomes," are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1 beta and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-kappa B and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-kappa B and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-kappa B and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-kappa B and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.