In addition to recognizing conserved molecular components of microbes (such as the endotoxin LPS), TLRs across the innate immune system respond to other cellular stressors called danger signals [13]. Danger signals include endogenous TLR agonists, such as high-mobility group box 1 (HMGB1) protein (Fig. 1). HMGB1 is a nuclear protein with cytokine-like actions that activates microglia-TLR signaling, further fueling expression of innate immune genes via activation of NF-κB, nuclear factor κ light-chain-enhancer of activated B cells (Fig. 1). Pro-inflammatory signals spread through signaling loops that amplify within and across peripheral and central immune cells. The extent to which CNS inflammation and immune gene expression rely on central or peripheral TLR4 signaling cascades remains unknown, but there is evidence for peripheral TLR4 signaling, at least partly, mediating CNS immune responses [14,15].
