Cellular mechanisms of toll-like receptor-3 activation in the thalamus are associated with white matter injury in the developing brain

Regina Vontell, Veena Supramaniam, Josephine Wyatt-Ashmead, Pierre Gressens, Mary Rutherford, Henrik Hagberg, Claire Thornton

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)273-285
Number of pages13
JournalJournal of neuropathology and experimental neurology
Volume74
Issue number3
DOIs
StatePublished - Mar 28 2015
Externally publishedYes

Keywords

  • Interferon regulatory factor-3
  • Microtubule-associated protein light chain
  • Toll-like receptor-3
  • White matter injury

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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