title: Activation of Toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development.
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.
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zurolo
authors.forename: Anand
authors.initials: A
authors.lastname: Iyer
authors.forename: Mattia
authors.initials: M
authors.lastname: Maroso
authors.forename: Caterina
authors.initials: C
authors.lastname: Carbonell
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Anink
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
authors.forename: Kees
authors.initials: K
authors.lastname: Fluiter
authors.forename: Wim G M
authors.initials: WG
authors.lastname: Spliet
authors.forename: Peter C
authors.initials: PC
authors.lastname: van Rijen
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002452:Cell Count; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004827:Epilepsy / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D054220:Malformations of Cortical Development / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D024243:HMGB1 Protein; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors