Physiology Department, Trinity College Institute for Neuroscience, Trinity College, Dublin 2, Ireland.
J Neuroinflammation. 2012 May 29;9:107. doi: 10.1186/1742-2094-9-107.
The interaction between the membrane glycoprotein, CD200 and its cognate receptor CD200 receptor (CD200R), has been shown to play a role in maintaining microglia in a quiescent state. There is evidence of increased activation under resting and stimulated conditions in microglia prepared from CD200-deficient mice compared with wild-type mice, whereas activation of the receptor by CD200 fusion protein (CD200Fc) ameliorates inflammatory changes which are evident in the central nervous system (CNS) of the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) and also in the hippocampus of aged rats. Additionally, an inverse relationship between microglial activation and expression of CD200 has been observed in animals treated with lipopolysaccharide (LPS) or amyloid-β (Aβ).
We assessed the effect of CD200R activation by CD200Fc on Aβ-induced production of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) and the expression of microglial activation markers, CD68 and CD40 in cultured glia. The role played by downstream of tyrosine kinase 2 (Dok2) phosphorylation in mediating the effects of CD200R activation was evaluated by siRNA knockdown of Dok2. To further examine the impact of inflammatory changes on synaptic plasticity, the effect of CD200Fc on Aβ-induced impairment of long-term potentiation (LTP) in the CA1 region of hippocampal slices was also investigated.
We demonstrate that Aβ-induced increases in IL-1β, TNFα, CD68 and CD40 were inhibited by CD200Fc. The evidence suggests that Dok2 phosphorylation is a key factor in mediating the effect of CD200Fc, since Dok2 knockdown by siRNA abrogated its effects on microglial activation and inflammatory cytokine production. Consistent with evidence that inflammatory changes negatively impact on LTP, we show that the Aβ-induced impairment of LTP was attenuated by CD200Fc.
The findings suggest that activation of CD200R and Dok2 is a valuable strategy for modulating microglial activation and may have therapeutic potential in neurodegenerative conditions.
膜糖蛋白 CD200 与其同源受体 CD200 受体（CD200R）的相互作用已被证明在维持小胶质细胞静止状态中发挥作用。有证据表明，与野生型小鼠相比，CD200 缺陷型小鼠制备的小胶质细胞在静息和受刺激条件下的激活增加，而 CD200 融合蛋白（CD200Fc）激活受体可改善多发性硬化症（MS）、实验性自身免疫性脑脊髓炎（EAE）小鼠模型的中枢神经系统（CNS）以及老年大鼠海马体中明显的炎症变化。此外，在接受脂多糖（LPS）或淀粉样β（Aβ）治疗的动物中观察到小胶质细胞激活与 CD200 表达之间呈负相关。
我们评估了 CD200Fc 对 Aβ诱导产生的促炎细胞因子白细胞介素 1β（IL-1β）和肿瘤坏死因子-α（TNFα）以及小胶质细胞激活标志物 CD68 和 CD40 的表达的影响。通过 siRNA 敲低酪氨酸激酶 2（Dok2）来评估 Dok2 磷酸化在介导 CD200R 激活作用中的作用。为了进一步研究炎症变化对突触可塑性的影响，还研究了 CD200Fc 对 Aβ诱导的海马切片 CA1 区长时程增强（LTP）损伤的影响。
我们证明 Aβ 诱导的 IL-1β、TNFα、CD68 和 CD40 的增加被 CD200Fc 抑制。证据表明，Dok2 磷酸化是介导 CD200Fc 作用的关键因素，因为 siRNA 敲低 Dok2 消除了其对小胶质细胞激活和炎症细胞因子产生的作用。与炎症变化对 LTP 产生负面影响的证据一致，我们表明 CD200Fc 减弱了 Aβ 诱导的 LTP 损伤。
这些发现表明，激活 CD200R 和 Dok2 是调节小胶质细胞激活的一种有价值的策略，在神经退行性疾病中可能具有治疗潜力。
