Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development

Emanuele Zurolo, Anand Iyer, Mattia Maroso, Caterina Carbonell, Jasper J. Anink, Teresa Ravizza, Kees Fluiter, Wim G M Spliet, Peter C. Van Rijen, Annamaria Vezzani, Eleonora Aronica

Research output: Contribution to journalArticle

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Abstract

Recent evidence in experimental models of seizures and in temporal lobe epilepsy support an important role of high-mobility group box 1 and toll-like receptor 4 signalling in the mechanisms of hyperexcitability leading to the development and perpetuation of seizures. In this study, we investigated the expression and cellular distribution of toll-like receptors 2 and 4, and of the receptor for advanced glycation end products, and their endogenous ligand high-mobility group box 1, in epilepsy associated with focal malformations of cortical development. Immunohistochemistry showed increased expression of toll-like receptors 2 and 4 and receptor for advanced glycation end products in reactive glial cells in focal cortical dysplasia, cortical tubers from patients with the tuberous sclerosis complex and in gangliogliomas. Toll-like receptor 2 was predominantly detected in cells of the microglia/macrophage lineage and in balloon cells in focal cortical dysplasia, and giant cells in tuberous sclerosis complex. The toll-like receptor 4 and receptor for advanced glycation end products were expressed in astrocytes, as well as in dysplastic neurons. Real-time quantitative polymerase chain reaction confirmed the increased receptors messenger RNA level in all pathological series. These receptors were not detected in control cortex specimens. In control cortex, high-mobility group box 1 was ubiquitously detected in nuclei of glial and neuronal cells. In pathological specimens, protein staining was instead detected in the cytoplasm of reactive astrocytes or in tumour astrocytes, as well as in activated microglia, predictive of its release from glial cells. In vitro experiments in human astrocyte cultures showed that nuclear to cytoplasmic translocation of high-mobility group box 1 was induced by interleukin-1β. Our findings provide novel evidence of intrinsic activation of these pro-inflammatory signalling pathways in focal malformations of cortical development, which could contribute to the high epileptogenicity of these developmental lesions.

Original languageEnglish
Pages (from-to)1015-1032
Number of pages18
JournalBrain
Volume134
Issue number4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

HMGB1 Protein
Malformations of Cortical Development
Toll-Like Receptor 4
Toll-Like Receptors
Toll-Like Receptor 2
Astrocytes
Neuroglia
Tuberous Sclerosis
Microglia
Seizures
Ganglioglioma
Temporal Lobe Epilepsy
Giant Cells
Interleukin-1
Real-Time Polymerase Chain Reaction
Epilepsy
Cytoplasm
Theoretical Models
Immunohistochemistry
Macrophages

Keywords

  • epilepsy
  • focal cortical dysplasia
  • glioneuronal tumours
  • inflammation
  • tuberous sclerosis complex

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Zurolo, E., Iyer, A., Maroso, M., Carbonell, C., Anink, J. J., Ravizza, T., ... Aronica, E. (2011). Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. Brain, 134(4), 1015-1032. https://doi.org/10.1093/brain/awr032

Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. / Zurolo, Emanuele; Iyer, Anand; Maroso, Mattia; Carbonell, Caterina; Anink, Jasper J.; Ravizza, Teresa; Fluiter, Kees; Spliet, Wim G M; Van Rijen, Peter C.; Vezzani, Annamaria; Aronica, Eleonora.

In: Brain, Vol. 134, No. 4, 04.2011, p. 1015-1032.

Research output: Contribution to journalArticle

Zurolo, E, Iyer, A, Maroso, M, Carbonell, C, Anink, JJ, Ravizza, T, Fluiter, K, Spliet, WGM, Van Rijen, PC, Vezzani, A & Aronica, E 2011, 'Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development', Brain, vol. 134, no. 4, pp. 1015-1032. https://doi.org/10.1093/brain/awr032
Zurolo, Emanuele ; Iyer, Anand ; Maroso, Mattia ; Carbonell, Caterina ; Anink, Jasper J. ; Ravizza, Teresa ; Fluiter, Kees ; Spliet, Wim G M ; Van Rijen, Peter C. ; Vezzani, Annamaria ; Aronica, Eleonora. / Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. In: Brain. 2011 ; Vol. 134, No. 4. pp. 1015-1032.
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