Department of Cellular and Molecular Neuroscience, Division of Neuroscience, Imperial College London, Hammersmith Campus, London, United Kingdom.
J Neurosci Res. 2010 Jun;88(8):1632-44. doi: 10.1002/jnr.22335.
Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6). Microglial conditioned medium (MGCM) from LPS-activated microglia attenuated primary OPC proliferation without inducing cell death. The microglial-induced inhibition of OPC proliferation was reversed by stimulating group III metabotropic glutamate receptors in microglia with the agonist L-AP4. In contrast to OPC, LPS-activated MGCM enhanced the survival of mature oligodendrocytes. Further investigation suggested that TNF and IL-6 released from TLR4-activated microglia might contribute to the effect of MGCM on OPC proliferation, insofar as TNF depletion of LPS-activated MGCM reduced the inhibition of OPC proliferation, and direct addition of TNF or IL-6 attenuated or increased proliferation, respectively. OPC themselves were also found to express proteins involved in TLR4 signalling, including TLR4, MyD88, and MAL. Although LPS stimulation of OPC did not induce proinflammatory cytokine release or affect their survival, it did trigger JNK phosphorylation, suggesting that TLR4 signalling in these cells is active. These findings suggest that OPC survival may be influenced not only by factors released from endotoxin-activated microglia but also through a direct response to endotoxins. This may have consequences for myelination under conditions in which microglial activation and cerebral infection are both implicated. , Inc.
激活的小胶质细胞可以通过释放细胞毒性因子来影响神经细胞的存活。在这里，我们研究了 Toll 样受体 4（TLR4）激活的小胶质细胞与少突胶质细胞或其前体细胞（OPC）之间的相互作用。用 TLR4 特异性脂多糖（LPS）孵育原代大鼠或 N9 小胶质细胞可激活丝裂原活化蛋白激酶，增加 CD68 和诱导型一氧化氮合酶的表达，并释放促炎细胞因子肿瘤坏死因子（TNF）和白细胞介素 6（IL-6）。LPS 激活的小胶质细胞的小胶质细胞条件培养基（MGCM）可减弱原代 OPC 的增殖，而不会诱导细胞死亡。用激动剂 L-AP4 刺激小胶质细胞中的 III 型代谢型谷氨酸受体可逆转小胶质细胞诱导的 OPC 增殖抑制。与 OPC 相反，LPS 激活的 MGCM 增强了成熟少突胶质细胞的存活。进一步的研究表明，TLR4 激活的小胶质细胞释放的 TNF 和 IL-6 可能有助于 MGCM 对 OPC 增殖的影响，因为 LPS 激活的 MGCM 中 TNF 的耗尽降低了对 OPC 增殖的抑制，而直接添加 TNF 或 IL-6 分别减弱或增加了增殖。还发现 OPC 本身也表达参与 TLR4 信号转导的蛋白，包括 TLR4、MyD88 和 MAL。尽管 LPS 刺激 OPC 不会诱导促炎细胞因子的释放或影响其存活，但它确实触发了 JNK 磷酸化，这表明这些细胞中的 TLR4 信号转导是活跃的。这些发现表明，OPC 的存活不仅可能受到内毒素激活的小胶质细胞释放的因子的影响，还可能通过对内毒素的直接反应受到影响。这可能对小胶质细胞激活和大脑感染都涉及的情况下的髓鞘形成产生影响。约翰威立父子公司。
