Lok Ker Zhing, Manzanero Silvia, Arumugam Thiruma V
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD9, 2 Medical Drive #04-01, Singapore 117597, Singapore; School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, QLD, Australia.
Brain Res. 2016 Aug 1;1644:192-202. doi: 10.1016/j.brainres.2016.05.023. Epub 2016 May 13.
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional and multi-ligand endocytic receptor abundantly expressed in neurons. Intravenous immunoglobulin (IVIg) is a purified preparation of plasma-derived human immunoglobulin used for the treatment of several neurological inflammatory disorders, and proposed for the treatment of stroke for its potent neuroprotective effects. LRP1 has been shown to be involved in the transcytosis of IVIg, and IVIg-LRP1 interaction leads to LRP1 tyrosine phosphorylation, which may contribute to the anti-inflammatory effects of IVIg. However, the question remains whether IVIg could induce its neuroprotective effects via LRP1 in neurons under ischemic stroke conditions. In cultured neurons and in a transient ischemic mouse model, ischemia decrease LRP1 levels and phosphorylation, and IVIg blocks these effects. In ischemic neurons, LRP1 antagonism by receptor associated protein (RAP) enhances the activation of pro-death signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and caspase-3, and IVIg reduces these effects. When applied to ischemic neuronal cultures, RAP induces a dramatic drop in Akt activation, and IVIg reverses this effect, as it does with the decrease in Bcl-2 levels caused by ischemic injury in the presence of RAP. Altogether, these results show evidence of LRP1 expression and activity modulation by IVIg, and support the role of LRP1 as a partner of IVIg in the execution of its neuroprotective effects.
低密度脂蛋白受体相关蛋白1（LRP1）是一种多功能、多配体的内吞受体，在神经元中大量表达。静脉注射免疫球蛋白（IVIg）是一种纯化的血浆源性人免疫球蛋白制剂，用于治疗多种神经炎症性疾病，并因其强大的神经保护作用而被提议用于治疗中风。已有研究表明LRP1参与IVIg的转胞吞作用，且IVIg与LRP1的相互作用会导致LRP1酪氨酸磷酸化，这可能有助于IVIg的抗炎作用。然而，问题仍然存在：在缺血性中风条件下，IVIg是否能通过LRP1在神经元中诱导其神经保护作用。在培养的神经元和短暂性缺血小鼠模型中，缺血会降低LRP1水平和磷酸化，而IVIg可阻断这些作用。在缺血神经元中，受体相关蛋白（RAP）对LRP1的拮抗作用会增强促死亡信号通路的激活，如核因子-κB（NF-κB）、丝裂原活化蛋白激酶（MAPKs）和半胱天冬酶-3，而IVIg可减轻这些作用。当应用于缺血性神经元培养物时，RAP会导致Akt激活急剧下降，而IVIg可逆转这种作用，就像它对RAP存在时缺血损伤引起的Bcl-2水平降低所起的作用一样。总之，这些结果表明了IVIg对LRP1表达和活性的调节作用，并支持LRP1作为IVIg在发挥其神经保护作用中的伙伴的作用。
