At least two other mechanisms may contribute to brain responses, oxidative stress and HMGB1-TLR signaling. NF-κB transcription is also activated by reactive oxygen species and we found increased expression of NOX and superoxide, another possible mechanism of amplification of brain proinflammatory responses. Yet another mechanism could involve HMGB1, a ubiquitous cytokine-like protein that is an agonist or co-agonist across multiple TLR and other innate immune receptors. HMGB1 is released by hyper-excitability, cytokines, cell damage, TLR receptor activation and other stimuli [52] (Figure 13). Recent studies have found that HMGB1 is required for TLR3 receptor signaling [22]. HMGB1 release and activation of TLR receptors represent another mechanism of brain proinflammatory amplification in addition to oxidative stress and brain cytokine increases.
