Innate immune-signaling cascades and evidence for upregulation in brain following AIE exposure. Innate immune-signaling cascades and evidence for upregulation in brain following AIE exposure. A simplified schematic of the TLR and RAGE signaling cascades. Stimulation of TLRs and RAGE with their endogenous agonist HMGB1 and other inflammagens [e.g., lipopolysaccharide (LPS)] leads to the generation of proinflammatory oxidases and reactive oxygen species (ROS) and downstream activation of NF-κB. Nuclear translocation of NF-κB leads to the secretion of proinflammatory gene expression, innate immune gene induction, cell death, and addiction-like behaviors. AP-1, activator protein-1; CD14, cluster of differentiation 14; ERK, extracellular signal-regulated kinase; IKK, inhibitor of nuclear factor κ-B; JNK, c-Jun N-terminal kinases; MyD88, myeloid differentiation primary response gene 88; Src, proto-oncogene tyrosine-protein kinase; TIRAP, Toll/interleukin-1 receptor domain-containing adaptor protein. Fulton T. Crews et al. Pharmacol Rev 2016;68:1074-1109 Copyright © 2016 by The Author(s)‏