Vontell Regina, Supramaniam Veena, Wyatt-Ashmead Josephine, Gressens Pierre, Rutherford Mary, Hagberg Henrik, Thornton Claire
From the Centre for the Developing Brain, Division of Imaging Sciences, and Biomedical Engineering, King's College London, King's Health Partners, St Thomas' Hospital (RV, VS, PG, MR, HH, CT); and Wigglesworth Perinatal Pathology Services, St Mary's Hospital (JW-A), London, United Kingdom; Perinatal Center, Departments of Physiology and Neuroscience and Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden (HH); and Inserm, U676, Paris, France (PG).
J Neuropathol Exp Neurol. 2015 Mar;74(3):273-85. doi: 10.1097/NEN.0000000000000172.
Toll-like receptor-3 (TLR3) has been identified in a variety of intracellular structures (e.g. endosomes and endoplasmic reticulum); it detects viral molecular patterns and damage-associated molecular patterns. We hypothesized that, after white matter injury (WMI) has occurred, localization and activation of TLR3 are altered in gray matter structures in response to damage-associated molecular patterns and activated glia. Therefore, we investigated the subcellular localization of TLR3 and its downstream signaling pathway in postmortem brain sections from preterm infants with and without WMI (7 patients each). We assessed astroglia (glial fibrillary acidic protein-positive), microglia (ionized calcium-binding adaptor molecule-1-positive), and neuronal populations in 3 regions of the thalamus and in the posterior limb of the internal capsule and analyzed TLR3 messenger RNA and protein expression in the ventral lateral posterior thalamic region, an area associated with impaired motor function. We also assessed TLR3 colocalization with late endosomes (lysosome-associated membrane protein-1) and phagosomal compartments in this region. Glial fibrillary acidic protein, ionized calcium-binding adaptor molecule-1, and TLR3 immunoreactivity and messenger RNA expression were increased in cases with WMI compared with controls. In ventral lateral posterior neurons, TLR3 was colocalized with the endoplasmic reticulum and the autophagosome, suggesting that autophagy may be a stress response associated with WMI. Thus, alterations in TLR3 expression in WMI may be an underlying molecular mechanism associated with impaired development in preterm infants.
Toll样受体3（TLR3）已在多种细胞内结构（如内体和内质网）中被鉴定出来；它能检测病毒分子模式和损伤相关分子模式。我们推测，在发生白质损伤（WMI）后，TLR3的定位和激活在灰质结构中会因损伤相关分子模式和活化的神经胶质细胞而发生改变。因此，我们研究了有和没有WMI的早产儿（各7例）尸检脑切片中TLR3的亚细胞定位及其下游信号通路。我们评估了丘脑3个区域和内囊后肢中的星形胶质细胞（胶质纤维酸性蛋白阳性）、小胶质细胞（离子钙结合衔接分子1阳性）和神经元群体，并分析了丘脑腹后外侧区域（与运动功能受损相关的区域）中TLR3信使核糖核酸和蛋白质的表达。我们还评估了该区域TLR3与晚期内体（溶酶体相关膜蛋白1）和吞噬小体区室的共定位情况。与对照组相比，WMI病例中的胶质纤维酸性蛋白、离子钙结合衔接分子1和TLR3免疫反应性及信使核糖核酸表达增加。在腹后外侧神经元中，TLR3与内质网和自噬体共定位，表明自噬可能是与WMI相关的应激反应。因此，WMI中TLR3表达的改变可能是与早产儿发育受损相关的潜在分子机制。
