Toll-Like Receptors in Pain and Itch
Pattern recognition receptors (PRR) are genetically encoded proteins which recognize a host of highly conserved “danger signals” produced by microbial organisms (pathogen-associated molecular patterns, or PAMPs) or released by damaged host cells (damage-associated molecular patterns, or DAMPs). PAMP or DAMP-mediated activation of PRR-bearing immune cells is a critical step in initiating an immune response. The Toll-like receptors (TLRs) are a small family of proteins with deep evolutionary origins; they are present in both invertebrate and vertebrate species and all TLR members share a common Toll-Interleukin-1 Receptor (TIR) domain. There is considerable variation in the number of TLRs present in different species with Drosophila (9), mice (12), and humans (10) each having a slightly different number which pales in comparison to the number present in purple sea urchins (222). In this chapter, we discuss the basic biology of the TLRs, including their activation, subcellular localization, and downstream signaling. We highlight the critical role that TLRs play in initiating innate and adaptive immune responses and emphasize a discussion of how TLR-mediated proinflammatory signaling is coupled to pain or itch through neuro-immune interactions. We also highlight emerging evidence that suggests TLR signaling in sensory neurons can rapidly modulate neuronal excitability and discuss the physiological consequences of non-canonical TLR signaling in neurons. Overall, this chapter reviews the plethora of evidence which now exists to support the many ways in which TLR signaling can regulate sensory function via neuro-immune interactions.
