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.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Prominent activation of complement, IL-1β, as well as overexpression of high mobility group box 1 and its cognate receptors (TLR2, TLR4, and receptor for advanced glycation end products), are other features of FCD II [77,120,176]. These observations provide evidence of a chronic inflammatory state in FCD II supporting the role of high mobility group box 1-TLR/receptor for advanced glycation end products pathways in the mechanisms underlying the intrinsic high epileptogenicity of these developmental lesions.…”

“…Accordingly, tubers are characterized by a complex activation of pro-inflammatory signaling pathways, including chemokines, complement, and IL-1β and TLRmediated pathways [135,176,199]. Activation of the plasminogen system [174] and focal BBB disruption [199] have been also described in tubers.…”

Astrocyte immune responses in epilepsy

“…The observation of prenatal TLRs and HMGB1 expression in giant cells within the tuber in TSC Samadani et al, 2007;Zurolo et al, 2011) suggests that the induction of these signaling pathways could be intrinsic to the developmental lesion per se, and that the development of seizures later in life could contribute to perpetuation of their activation.…”

Epilepsy and the inflammasome: Targeting inflammation as a novel therapeutic strategy for seizure disorders

“…In addition, IL-1β itself can induce HMGB1 release [20], and together, IL-1β and HMGB1 have been shown to act synergistically to release IL-6 from synovial fibroblasts [21]. This suggests that targeting the NLRP3 inflammasome may provide a means to abolish this inflammatory circuit; and targeting upstream of both IL-1β and HMGB1 in this way may achieve a more diverse antiinflammatory effect over targeting further down the IL-1 cascade (i.e.…”