Departments of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Mol Cell Neurosci. 2010 Nov;45(3):234-44. doi: 10.1016/j.mcn.2010.06.014. Epub 2010 Jun 28.
Fine regulation of the innate immune response following brain injury or infection is important to avoid excessive activation of microglia and its detrimental consequences on neural cell viability and function. To get insights on the molecular networks regulating microglia activation, we analyzed expression, regulation and functional relevance of tumor necrosis factor receptors (TNFR) 2 in cultured mouse microglia. We found that microglia upregulate TNFR2 mRNA and protein and shed large amounts of soluble TNFR2, but not TNFR1, in response to pro-inflammatory stimuli and through activation of TNFR2 itself. By microarray analysis, we demonstrate that TNFR2 stimulation in microglia regulates expression of genes involved in immune processes, including molecules with anti-inflammatory and neuroprotective function like granulocyte colony-stimulating factor, adrenomedullin and IL-10. In addition, we identify IFN-γ as a regulator of the balance between pro- and anti-inflammatory/neuroprotective factors induced by TNFR2 stimulation. These data indicate that, through TNFR2, microglia may contribute to the counter-regulatory response activated in neuropathological conditions.
精细调控脑损伤或感染后的固有免疫反应对于避免小胶质细胞过度激活及其对神经细胞存活和功能的有害影响非常重要。为了深入了解调控小胶质细胞激活的分子网络，我们分析了培养的小鼠小胶质细胞中肿瘤坏死因子受体（TNFR）2 的表达、调控和功能相关性。我们发现，小胶质细胞在受到促炎刺激和通过 TNFR2 自身激活时，会上调 TNFR2 mRNA 和蛋白，并大量释放可溶性 TNFR2，但不会释放 TNFR1。通过微阵列分析，我们证明 TNFR2 刺激可调节小胶质细胞中参与免疫过程的基因表达，包括具有抗炎和神经保护功能的分子，如粒细胞集落刺激因子、肾上腺髓质素和 IL-10。此外，我们还发现 IFN-γ 是 TNFR2 刺激诱导的促炎/抗炎/神经保护因子平衡的调节剂。这些数据表明，小胶质细胞通过 TNFR2 可能有助于在神经病理条件下激活的代偿性反应。
