Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring.
Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring.
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TLR4 对母体 LPS 暴露诱导的小胶质细胞激活导致后代 ASD 样行为的关键作用
DOI：
10.3389/fcell.2021.634837
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Xiao L;Yan J;Feng D;Ye S;Yang T;Wei H;Li T;Sun W;Chen J
目的：目的探讨TLR 4在母体脂多糖（LPS）暴露诱导子代自闭症样行为中前额叶皮质小胶质细胞活化中的作用。方法：妊娠TLR 4 −/−（敲除，KO）和WT（野生型，WT）母鼠分别腹腔注射LPS或PBS。采用ELISA法检测LPS暴露后母血和胎脑中TNFα、IL-1β和IL-6的水平。对妊娠期、窝仔数和仔鼠体重进行评价。在7周龄时，采用三腔室社交性测试、旷场测试和嗅觉习惯/不习惯测试评估子代的自闭症样行为。Western blotting检测TLR 4、Phospho-NFκB p65、IKKα、IBA-1、iNOS、Arg-1、C3、CR 3A、NMDAR 2A和Syn-1在前额叶皮质的表达水平。免疫荧光染色观察小胶质细胞的形态学变化及TLR 4的分布和表达。用Golgi-Cox染色法观察2周龄仔鼠神经元树突长度和棘密度。结果：母体LPS刺激可使WT小鼠血清TNFα、IL-6及胎脑TNFα水平升高。母体LPS处理后，WT后代的窝仔数和体重显著降低。LPS处理的WT后代具有较低的社会和自我探索行为，以及更大的焦虑和重复行为。LPS处理的WT后代中TLR 4信号通路的蛋白表达水平（包括TLR 4、Phospho-NFκB p65、IKKα和IBA-1）、iNOS表达增加，而Arg-1降低。母体LPS处理导致突触修剪相关蛋白C3和CR 3A的水平显著降低。此外，WT后代的神经元树突长度和棘密度以及突触可塑性相关蛋白NMDAR 2A和Syn-1的表达水平降低;然而，妊娠期LPS暴露对TLR 4 −/−后代没有影响。结论：母体LPS暴露后TLR 4信号通路的激活诱导了小胶质细胞的异常激活，这反过来又参与了过度的突触修剪，从而降低了后代的突触可塑性。这可能是子代小鼠出现自闭症样行为的原因之一。
Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure. Methods: Pregnant TLR4−/− (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring. Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4−/− offspring. Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.
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影响因子：
3.7
作者：
Hines DJ;Choi HB;Hines RM;Phillips AG;MacVicar BA
通讯作者：
MacVicar BA
影响因子：
15.1
作者：
Montesinos, Jorge;Pascual, Maria;Guerri, Consuelo
通讯作者：
Guerri, Consuelo
Toll像受体（TLR）自由基周期在慢性炎症中的作用：针对TLR4途径的可能治疗方法。
影响因子：
5.1
作者：
Lucas K;Maes M
通讯作者：
Maes M
影响因子：
6.2
作者：
Edmonson C;Ziats MN;Rennert OM
通讯作者：
Rennert OM
影响因子：
5.3
作者：
Meyer, U;Nyffeler, M;Feldon, J
通讯作者：
Feldon, J