title: Cellular mechanisms of toll-like receptor-3 activation in the thalamus are associated with white matter injury in the developing brain.
abstract: 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.
authors: 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).
authors: Regina
authors: R
authors: Vontell
authors: Veena
authors: V
authors: Supramaniam
authors: Josephine
authors: J
authors: Wyatt-Ashmead
authors: Pierre
authors: P
authors: Gressens
authors: Mary
authors: M
authors: Rutherford
authors: Henrik
authors: H
authors: Hagberg
authors: Claire
authors: C
authors: Thornton
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D062071:Infant, Extremely Premature / Q000378:metabolism*; D007231:Infant, Newborn; D010865:Pilot Projects; D011446:Prospective Studies; D013788:Thalamus / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis*; D066127:White Matter / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology
chemical_list: C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3