Cellular Mechanisms of Toll-Like Receptor-3 Activation in the Thalamus Are Associated With White Matter Injury in the Developing Brain

TY - JOUR

T1 - Cellular Mechanisms of Toll-Like Receptor-3 Activation in the Thalamus Are Associated With White Matter Injury in the Developing Brain

AU - Vontell, Regina

AU - Supramaniam, Veena

AU - Wyatt-Ashmead, Josephine

AU - Gressens, Pierre

AU - Rutherford, Mary

AU - Hagberg, Henrik

AU - Thornton, Claire

PY - 2015

Y1 - 2015

N2 - 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 postmortembrain 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, alterationsin TLR3 expression in WMI may be an underlying molecular mechanism associated with impaired development in preterm infants.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

AB - 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 postmortembrain 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, alterationsin TLR3 expression in WMI may be an underlying molecular mechanism associated with impaired development in preterm infants.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

U2 - 10.1097/NEN.0000000000000172

DO - 10.1097/NEN.0000000000000172

M3 - Article

C2 - 25668563

SN - 0022-3069

JO - Journal of Neuropathology and Experimental Neurology

JF - Journal of Neuropathology and Experimental Neurology

ER -