Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore, Singapore.
Department of Pharmacology, National University of Singapore, Singapore, Singapore.
Mol Neurobiol. 2018 Feb;55(2):1082-1096. doi: 10.1007/s12035-017-0394-9. Epub 2017 Jan 14.
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)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB 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-κB 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-κB 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-κB 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.
多蛋白复合物，称为“炎性小体”，已知在缺血性中风后导致神经元细胞死亡和脑损伤。缺血性中风增加神经元中核苷酸结合寡聚化结构域（NOD）样受体（NLR）吡喃结构域包含 1 和 3（NLRP1 和 NLRP3）炎性小体蛋白以及白细胞介素（IL）-1β和 IL-18 的表达和激活。在这项研究中，我们提供的证据表明，NF-κB 和 MAPK 信号通路的激活部分负责诱导 NLRP1 和 NLRP3 炎性小体蛋白的表达和激活，并且这些作用可以分别在体外和体内缺血条件下使用这些两种途径的药理学抑制剂在神经元和脑组织中减弱。此外，这些发现提供了支持性证据，表明静脉内免疫球蛋白（IVIg）制剂的治疗可以减少 NF-κB 和 MAPK 信号通路的激活，从而导致 NLRP1 和 NLRP3 炎性小体的表达和激活减少，以及在体外和体内缺血条件下增加抗凋亡蛋白 Bcl-2 和 Bcl-xL 的表达。总之，这些结果提供了令人信服的证据，表明 NF-κB 和 MAPK 信号通路在调节缺血条件下原代皮质神经元和脑组织中 NLRP1 和 NLRP3 炎性小体的表达和激活中起关键作用。此外，IVIg 制剂的治疗降低了 NF-κB 和 MAPK 信号通路的激活，从而减轻了缺血条件下原代皮质神经元中 NLRP1 和 NLRP3 炎性小体的表达和激活。因此，这些发现表明，针对神经元中炎性小体激活的治疗干预可能为缺血性中风的未来治疗提供新的机会。
