Computational modeling of cytokine signaling in microglia.
Computational modeling of cytokine signaling in microglia.
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小胶质细胞细胞因子信号传导的计算模型。
DOI：
10.1039/c5mb00488h
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发表时间：
2015-12
影响因子：
--
通讯作者：
Vadigepalli R
中科院分区：
文献类型：
--
作者：
Anderson WD;Makadia HK;Greenhalgh AD;Schwaber JS;David S;Vadigepalli R
由于神经胶质活化引起的神经炎症与许多CNS疾病有关。我们建立了一个小胶质细胞细胞因子相互作用网络的计算模型来研究小胶质细胞介导的神经炎症的调控机制。我们建立了一个基于文献的细胞因子网络，包括TNFα、TGFβ和IL-10，并将一个数学模型拟合到来自LPS处理的小胶质细胞的已发表数据。为了解释实验数据，需要在我们的模型中加入一个以前未报道的TGFβ自动调节环。全局敏感性分析显示，TGFβ和IL-10介导的TNFα抑制对于调节网络行为至关重要。我们评估了LPS诱导的TNFα反应特征对初始TGFβ和IL-10水平的敏感性。分析显示，初始条件空间的不同区域内有两个相对变化的TNFα反应谱。进一步分析表明TNFα对持续的LPS刺激表现出适应性。我们模拟了功能性抑制TGFβ和IL-10对TNFα适应的影响。我们的分析表明，TGFβ和IL-10敲除（TGFβ KO和IL-10 KO）对适应产生不同的影响。TFGβ KO减弱TNFα适应，而IL-10 KO增强TNFα适应。我们通过实验验证了IL-10 KO增强小鼠巨噬细胞中TNFα适应的假设，并找到了支持证据。这些相反的效果可以解释为微分动力学的负反馈。抑制IL-10可减少导致TNFα介导的TGFβ表达增强的早期负反馈。我们提出，差分动力学在平行的负反馈回路构成了一个新的机制，复杂的和非直观的亲与个别细胞因子扰动的抗炎作用。
Neuroinflammation due to glial activation has been linked to many CNS diseases. We developed a computational model of a microglial cytokine interaction network to study the regulatory mechanisms of microglia-mediated neuroinflammation. We established a literature-based cytokine network, including TNFα, TGFβ, and IL-10, and fitted a mathematical model to published data from LPS-treated microglia. The addition of a previously unreported TGFβ autoregulation loop to our model was required to account for experimental data. Global sensitivity analysis revealed that TGFβ- and IL-10-mediated inhibition of TNFα was critical for regulating network behavior. We assessed the sensitivity of the LPS-induced TNFα response profile to the initial TGFβ and IL-10 levels. The analysis showed two relatively shifted TNFα response profiles within separate domains of initial condition space. Further analysis revealed that TNFα exhibited adaptation to sustained LPS stimulation. We simulated the effects of functionally inhibiting TGFβ and IL-10 on TNFα adaptation. Our analysis showed that TGFβ and IL-10 knockouts (TGFβ KO and IL-10 KO) exert divergent effects on adaptation. TFGβ KO attenuated TNFα adaptation whereas IL-10 KO enhanced TNFα adaptation. We experimentally tested the hypothesis that IL-10 KO enhances TNFα adaptation in murine macrophages and found supporting evidence. These opposing effects could be explained by differential kinetics of negative feedback. Inhibition of IL-10 reduced early negative feedback that results in enhanced TNFα-mediated TGFβ expression. We propose that differential kinetics in parallel negative feedback loops constitute a novel mechanism underlying the complex and non-intuitive pro- versus anti-inflammatory effects of individual cytokine perturbations.
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影响因子：
19.6
作者：
通讯作者：
--
影响因子：
4.3
作者：
An GC;Faeder JR
通讯作者：
Faeder JR
影响因子：
7.3
作者：
Cheng CS;Feldman KE;Lee J;Verma S;Huang DB;Huynh K;Chang M;Ponomarenko JV;Sun SC;Benedict CA;Ghosh G;Hoffmann A
通讯作者：
Hoffmann A
DOI：
10.1006/clin.1995.1163
发表时间：
1995-12-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
CHAO, CC;HU, SX;PETERSON, PK
通讯作者：
PETERSON, PK
影响因子：
5.3
作者：
Bilbo, SD;Biedenkapp, JC;Maier, SF
通讯作者：
Maier, SF