Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
J Neurochem. 2012 Jan;120(1):93-105. doi: 10.1111/j.1471-4159.2011.07541.x. Epub 2011 Nov 17.
Increasing evidences suggest that neuropeptide Y (NPY) may act as a key modulator of the cross-talk between the brain and the immune system in health and disease. In the present study, we dissected the possible inhibitory role of NPY upon inflammation-associated microglial cell motility. NPY, through activation of Y(1) receptors, was found to inhibit lipopolysaccharide (LPS)-induced microglia (N9 cell line) motility. Moreover, stimulation of microglia with LPS was inhibited by IL-1 receptor antagonist (IL-1ra), suggesting the involvement of endogenous interleukin-1 beta (IL-1β) in this process. Direct stimulation with IL-1β promoted downstream p38 mitogen-activated protein kinase mobilization and increased microglia motility. Moreover, consistently, p38 mitogen-activated protein kinase inhibition decreased the extent of actin filament reorganization occurring during plasma membrane ruffling and p38 phosphorylation was inhibited by NPY, involving Y(1) receptors. Significantly, the key inhibitory role of NPY on LPS-induced motility of CD11b-positive cells was further confirmed in mouse brain cortex explants. In summary, we revealed a novel functional role for NPY in the regulation of microglial function that may have important implications in the modulation of CNS injuries/diseases where microglia migration/motility might play a role.
越来越多的证据表明，神经肽 Y（NPY）可能在健康和疾病中作为大脑和免疫系统之间相互作用的关键调节剂发挥作用。在本研究中，我们剖析了 NPY 对炎症相关小胶质细胞迁移的可能抑制作用。通过激活 Y1 受体，NPY 被发现可抑制脂多糖（LPS）诱导的小胶质细胞（N9 细胞系）迁移。此外，LPS 刺激小胶质细胞被白细胞介素-1 受体拮抗剂（IL-1ra）抑制，表明内源性白细胞介素-1β（IL-1β）参与了这一过程。IL-1β 的直接刺激促进了下游 p38 丝裂原活化蛋白激酶的动员，并增加了小胶质细胞的迁移。此外，p38 丝裂原活化蛋白激酶的抑制一致地减少了在质膜隆起过程中发生的肌动蛋白丝重排的程度，并且 NPY 抑制了 p38 的磷酸化，涉及 Y1 受体。重要的是，NPY 对 LPS 诱导的 CD11b 阳性细胞迁移的关键抑制作用在小鼠大脑皮质外植体中得到了进一步证实。综上所述，我们揭示了 NPY 在调节小胶质细胞功能方面的新功能作用，这可能对中枢神经系统损伤/疾病的调节具有重要意义，其中小胶质细胞迁移/运动可能起作用。
