Neuronal expression of CD22: Novel mechanism for inhibiting microglial proinflammatory cytokine production
Neuronal expression of CD22: Novel mechanism for inhibiting microglial proinflammatory cytokine production
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作者：
Mott, RT;Ait-Ghezala, G;Tan, J
尽管中枢神经系统（CNS）被认为是免疫特权部位，但它可以表现出显着的炎症反应，这可能在许多神经系统疾病中发挥致病作用。小胶质细胞似乎是特别重要的启动和维持中枢神经系统炎症。这些细胞在正常CNS中以静止形式存在，但在用炎性物质如脂多糖（LPS）刺激后获得巨噬细胞样性质（包括主动吞噬作用、抗原呈递所必需的蛋白质的上调和促炎细胞因子的产生）。最近的研究集中在阐明神经元在小胶质细胞炎症反应调节中的作用。在本研究中，我们证明，使用神经元-小胶质细胞共培养，神经元能够抑制LPS诱导的肿瘤坏死因子-α（TNF-α）的小胶质细胞的生产。这种抑制似乎依赖于轴突末端的物质分泌，因为用突触前钙通道阻断剂ω-芋螺毒素处理消除了这种抑制作用。此外，我们表明，条件培养基从神经元培养物同样抑制小胶质细胞TNF-α的生产，这提供了额外的证据，神经元分泌抑制物质。我们之前已经证明跨膜蛋白-酪氨酸磷酸酶CD 45在负调节小胶质细胞活化方面发挥着重要作用。最近的表征CD 22作为这种受体的内源性配体导致我们研究神经元是否表达这种蛋白质。事实上，我们能够证明CD 22 mRNA和蛋白质表达在培养的神经元和小鼠大脑，使用逆转录酶-聚合酶链反应和抗体为基础的技术。此外，我们发现，神经元分泌CD 22，其功能作为小胶质细胞促炎细胞因子产生的抑制剂。(C)2004威利-利斯公司
Although considered an immunologically privileged site, the central nervous system (CNS) can display significant inflammatory responses, which may play a pathogenic role in a number of neurological diseases. Microglia appear to be particularly important for initiating and sustaining CNS inflammation. These cells exist in a quiescent form in the normal CNS, but acquire macrophage-like properties (including active phagocytosis, upregulation of proteins necessary for antigen presentation, and production of proinflammatory cytokines) after stimulation with inflammatory substances such as lipopolysaccharide (LPS). Recent studies have focused on elucidating the role of neurons in the regulation of microglial inflammatory responses. In the present study, we demonstrate, using neuron-microglial cocultures, that neurons are capable of inhibiting LPS-induced tumor necrosis factor-alpha (TNF-alpha) production by microglia. This inhibition appears to be dependent on secretion of substances at axon terminals, as treatment with the presynaptic calcium channel blocker omega-conotoxin abolishes this inhibitory effect. Moreover, we show that conditioned medium from neuronal cultures similarly inhibits microglial TNF-a production, which provides additional evidence that neurons secrete inhibitory substances. We previously demonstrated that the transmembrane protein-tyrosine phosphatase CD45 plays an important role in negatively regulating microglial activation. The recent characterization of CD22 as an endogenous ligand of this receptor led us to investigate whether neurons express this protein. Indeed, we were able to demonstrate CD22 mRNA and protein expression in cultured neurons and mouse brain, using reverse transcriptase-polymerase chain reaction and antibody-based techniques. Furthermore, we show that neurons secrete CD22, which functions as an inhibitor of microglial proinflammatory cytokine production. (C) 2004 Wiley-Liss, Inc.