Microglial activation is believed to play a role in many psychiatric and neurodegenerative diseases. Based largely on evidence from other cell types, it is widely thought that MAP kinase (ERK, JNK and p38) signalling pathways contribute strongly to microglial activation following immune stimuli acting on toll-like receptor (TLR) 3 or TLR4. We report here that exposure of SimA9 mouse microglial cell line to immune mimetics stimulating TLR4 (lipopolysaccharide—LPS) or TLR7/8 (resiquimod/R848), results in marked MAP kinase activation, followed by induction of nitric oxide synthase, and various cytokines/chemokines. However, in contrast to TLR4 or TLR7/8 stimulation, very few effects of TLR3 stimulation by poly-inosine/cytidine (polyI:C) were detected. Induction of chemokines/cytokines at the mRNA level by LPS and resiquimod were, in general, only marginally affected by MAP kinase inhibition, and expression of TNF, Ccl2 and Ccl5 mRNAs, along with nitrite production, were enhanced by p38 inhibition in a stimulus-specific manner. Selective JNK inhibition enhanced Ccl2 and Ccl5 release. Many distinct responses to stimulation of TLR4 and TLR7 were observed, with JNK mediating TNF protein induction by the latter but not the former, and suppressing Ccl5 release by the former but not the latter. These data reveal complex modulation by MAP kinases of microglial responses to immune challenge, including a dampening of some responses. They demonstrate that abnormal levels of JNK or p38 signalling in microglial cells will perturb their profile of cytokine and chemokine release, potentially contributing to abnormal inflammatory patterns in CNS disease states.

小胶质细胞活化被认为在许多精神疾病和神经退行性疾病中发挥作用。主要基于来自其他细胞类型的证据，人们普遍认为 MAP 激酶（ERK、JNK 和 p38）信号通路在免疫刺激作用于 toll 样受体 (TLR) 3 或 TLR4 后强烈促进小胶质细胞活化。我们在此报告将 SimA9 小鼠小胶质细胞系暴露于刺激 TLR4（脂多糖-LPS）或 TLR7/8（瑞喹莫德/R848）的免疫模拟物，导致显着的 MAP 激酶活化，随后诱导一氧化氮合酶和各种细胞因子/趋化因子。然而，与 TLR4 或 TLR7/8 刺激相比，聚肌苷/胞苷 (polyI:C) 对 TLR3 刺激的影响非常少。LPS 和瑞喹莫特在 mRNA 水平上对趋化因子/细胞因子的诱导通常是TNF、Ccl2和Ccl5 mRNAs 以及亚硝酸盐的产生通过 p38 抑制以一种刺激特异性的方式得到增强。选择性 JNK 抑制增强了 Ccl2 和 Ccl5 的释放。观察到对 TLR4 和 TLR7 刺激的许多不同反应，JNK 介导后者而不是前者对 TNF 蛋白的诱导，并抑制前者而不是后者的 Ccl5 释放。这些数据揭示了 MAP 激酶对小胶质细胞对免疫挑战的反应的复杂调节，包括抑制某些反应。他们证明，小胶质细胞中异常水平的 JNK 或 p38 信号传导将扰乱其细胞因子和趋化因子释放的特征，可能导致中枢神经系统疾病状态下的异常炎症模式。