Primary Cortical Cell Tri-Culture-Based Screening of Neuroinflammatory Response in Toll-like Receptor Activation.
Primary Cortical Cell Tri-Culture-Based Screening of Neuroinflammatory Response in Toll-like Receptor Activation.
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DOI：
10.3390/biomedicines10092122
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发表时间：
2022-08-29
期刊：
影响因子：
4.7
通讯作者：
Seker, Erkin
中科院分区：
文献类型：
--
作者：
Goshi, Noah;Kim, Hyehyun;Seker, Erkin
Toll样受体（TLR）在中枢神经系统（CNS）中的激活可导致神经炎症并导致许多神经系统疾病，包括自身免疫性疾病。细胞培养模型是研究导致这些疾病状态的特定分子和细胞机制以及识别潜在治疗方法的有力工具。然而，大多数细胞培养模型在捕获生物学相关现象方面具有局限性，部分原因是不包含必要的细胞类型。神经元、星形胶质细胞和小胶质细胞（在神经炎症中起作用的关键细胞类型）都表达至少一个TLR子集。然而，这些细胞类型中的每一种对各种TLR活化的反应，沿着它们对神经炎症过程的相对贡献，还远不清楚。在这项研究中，我们证明了筛选能力的原代皮层细胞三文化的神经元，星形胶质细胞和小胶质细胞从新生大鼠。具体来说，我们比较了三文化的神经炎症反应的原代神经元-星形胶质细胞共培养的一套已知的TLR激动剂。我们证明，小胶质细胞是必要的神经毒性神经炎症反应，如增加细胞死亡和凋亡，在TLR 2，3，4和7/8激活的观察。此外，我们表明，TLR 3激动剂治疗后，小胶质细胞和星形胶质细胞在神经炎症反应中发挥相反的作用，并且观察到的反应是由TLR 3激活的程度决定的。总体而言，我们证明，小胶质细胞发挥显着的作用，在体外TLR激活的神经炎症反应，因此，三文化有潜力作为一个筛选平台，更好地复制体内反应。
The activation of toll-like receptors (TLRs) in the central nervous system (CNS) can lead to neuroinflammation and contribute to many neurological disorders, including autoimmune diseases. Cell culture models are powerful tools for studying specific molecular and cellular mechanisms that contribute to these disease states and identifying potential therapeutics. However, most cell culture models have limitations in capturing biologically relevant phenomena, due in part to the non-inclusion of necessary cell types. Neurons, astrocytes, and microglia (critical cell types that play a role in neuroinflammation) all express at least a subset of TLRs. However, the response of each of these cell types to various TLR activation, along with their relative contribution to neuroinflammatory processes, is far from clear. In this study, we demonstrate the screening capabilities of a primary cortical cell tri-culture of neuron, astrocyte, and microglia from neonatal rats. Specifically, we compare the neuroinflammatory response of tri-cultures to that of primary neuron-astrocyte co-cultures to a suite of known TLR agonists. We demonstrate that microglia are required for observation of neurotoxic neuroinflammatory responses, such as increased cell death and apoptosis, in response to TLR2, 3, 4, and 7/8 activation. Additionally, we show that following TLR3 agonist treatment, microglia and astrocytes play opposing roles in the neuroinflammatory response, and that the observed response is dictated by the degree of TLR3 activation. Overall, we demonstrate that microglia play a significant role in the neuroinflammatory response to TLR activation in vitro and, hence, the tri-culture has the potential to serve as a screening platform that better replicates the in vivo responses.
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