Regulation of IL-6 Secretion by Astrocytes via TLR4 in the Fragile X Mouse Model.
Regulation of IL-6 Secretion by Astrocytes via TLR4 in the Fragile X Mouse Model.
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DOI：
10.3389/fnmol.2018.00272
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发表时间：
2018
影响因子：
4.8
通讯作者：
Doering LC
中科院分区：
文献类型：
--
作者：
Krasovska V;Doering LC
脆性X综合征（FXS）是由异常树突形态和改变突触蛋白表达确定的。星形胶质细胞分泌的因子如腱生蛋白C（TNC）可能有助于突触的变化，包括突触的成熟。TNC是已知的toll样受体4（TLR 4）的内源性配体，其已显示诱导促炎细胞因子如白介素-6（IL-6）的表达。在分子水平上，升高的IL-6促进兴奋性突触形成并增加树突棘长度。通过这些与FXS表型相关的分子变化，我们研究了内源性TLR 4激活剂TNC及其下游靶点IL-6在脆性X智力低下1（FMR 1）敲除（KO）小鼠模型星形胶质细胞中的表达和机制。FMR 1 KO星形胶质细胞分泌的TNC和IL-6显著增加。加入TNC和脂多糖（LPS）诱导IL-6的分泌，而TLR 4的拮抗剂（LPS-RS）有相反的效果。出生后FMR 1基因敲除小鼠皮质TNC和IL-6蛋白表达也显著升高。此外，与接种野生型星形胶质细胞的培养基相比，接种来自FMR 1 KO星形胶质细胞的星形胶质细胞条件培养基（ACM）时，野生型（WT）和FMR 1 KO神经元的囊泡谷氨酸转运蛋白1（VGLUT 1）/突触后密度蛋白95（PSD 95）阳性突触斑点数量增加。通过评估所涉及的细胞机制，可以提供一种新的治疗选择，以靶向FXS中观察到的突触功能异常。
Fragile X syndrome (FXS) is identified by abnormal dendrite morphology and altered synaptic protein expression. Astrocyte secreted factors such as Tenascin C (TNC), may contribute to the synaptic changes, including maturation of the synapse. TNC is a known endogenous ligand of toll-like receptor 4 (TLR4) that has been shown to induce the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). At the molecular level, elevated IL-6 promotes excitatory synapse formation and increases dendrite spine length. With these molecular changes linked to the phenotype of FXS, we examined the expression and the mechanism of the endogenous TLR4 activator TNC, and its downstream target IL-6 in astrocytes from the Fragile X Mental Retardation 1 (FMR1) knockout (KO) mouse model. Secreted TNC and IL-6 were significantly increased in FMR1 KO astrocytes. Addition of TNC and lipopolysaccharide (LPS) induced IL-6 secretion, whereas the antagonist of TLR4 (LPS-RS) had an opposing effect. Cortical protein expression of TNC and IL-6 were also significantly elevated in the postnatal FMR1 KO mouse. In addition, there was an increase in the number of vesicular glutamate transporter 1 (VGLUT1)/post synaptic density protein 95 (PSD95) positive synaptic puncta of both wild-type (WT) and FMR1 KO neurons when plated with astrocyte conditioned media (ACM) from FMR1 KO astrocytes, compared to those plated with media from wild type astrocytes. By assessing the cellular mechanisms involved, a novel therapeutic option could be made available to target abnormalities of synaptic function seen in FXS.
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DOI：
10.1016/s1091-8531(98)90087-8
发表时间：
1998-10-01
期刊：
Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus
影响因子：
--
作者：
Hatton, D D;Buckley, E;Roberts, J
通讯作者：
Roberts, J
脆弱的X小鼠小脑中持续的星形胶质细胞激活。
影响因子：
3.1
作者：
Pacey LK;Guan S;Tharmalingam S;Thomsen C;Hampson DR
通讯作者：
Hampson DR
影响因子：
3.1
作者：
Jones EV;Bouvier DS
通讯作者：
Bouvier DS
影响因子：
3.7
作者：
Gatto CL;Broadie K
通讯作者：
Broadie K
DOI：
10.1007/978-3-642-21649-7_14
发表时间：
2012-01-01
期刊：
MODELING FRAGILE X SYNDROME
影响因子：
--
作者：
Hunsaker, Michael R.;Arque, Gloria;Hukema, Renate K.
通讯作者：
Hukema, Renate K.