Fig. 2

Summary of three key signaling cascades that may mediate the link between inflammation and epileptogenesis. HMGB1, IL-1β, TGF-β, and serum albumin have varied release mechanisms from multiple cell types in order to activate their signaling pathways. After injury, HMGB1 may be passively released from necrotic neurons to the extracellular space, or released actively from activated microglia and astrocytes. HMGB1 can bind to multiple receptors on many different cell types, such as TLR4, which can activate MyD88 independent pathways such as the phosphorylation of interferon regulatory transcription factor 3 (IRF3) leading to the transcription and release of interferons-α and -β, as well as other interferon-induced genes. HMGB1-TLR4 can also activate NF-κB signaling both directly or via TNF receptor-associated factor 6 (TRAF6). This can lead to a rapid nuclear transcription of various immune-related processes, as reviewed elsewhere [250]. Caspase-1 mediates cleavage of inactive pro-IL-1β to active IL-1β, allowing for its relocation into the extracellular space, where IL-1β can bind to IL-1R1 either directly or in complex with HMGB1. The IL-1β/IL-1R1 complex can then induce NF-κB signaling via TRAF6 or activate MyD88-dependent MAPK signaling, which has been linked to the production of various neurotoxic molecules. TGF-β is released in an inactive form from cells and binds to the extracellular matrix. Proteases, released after injury, cleave the inactive protein to active TGF-β, which is able to bind to the two TGF-β receptors. Mechanical breakdown of the BBB allows serum albumin into the extracellular space, where it can also bind to TGF-β receptor1 and receptor2, which signal via Smad complex proteins or MAPK signaling pathways, respectively, to regulate the immune response. This pathway has also been implicated in post-translational changes to a variety of voltage-dependent ion channels implicated in changes to neuronal excitability [94]