Toll-like receptors (TLRs) are best known for their roles in controlling innate immunity (Akira et al. 2006). TLRs are characterized as pattern-recognition receptors (PRRs) to initiate innate immune responses via recognition of pathogen-associated molecular patterns (PAMPs) (Akira et al. 2006). TLRs can also sense endogenous molecules that are released after cellular stress or tissue injury, known as danger-associated molecular patterns (DAMPs). Activation of TLRs in immune cells leads to the synthesis of various proinflammatory cytokines and chemokines via transcriptional regulation. TLRs-mediated innate immune responses are also a prerequisite for the generation of adaptive immune responses (Mills 2011). Thus, TLRs represent the first line of host defense against pathogens and play a key role in both innate and adaptive immunity (Akira et al. 2006).

TLRs are also found to be expressed by various cell types in the central nervous system (CNS) and peripheral nervous system (PNS), such as microglia, astrocytes, oligodendrocytes, Schwann cells, and neurons (Okun et al. 2011; Buchanan et al. 2010; Lehnardt 2010). Activation of TLR signaling in the CNS also results in the production of inflammatory cytokines, enzymes, and other inflammatory mediators, which contributes to the pathogenesis of CNS microbial infection (Suh et al. 2009) as well as noninfective disorders, such as stroke (Caso et al. 2007), Alzheimer’s disease (AD) (Tahara et al. 2006), multiple sclerosis (MS) (Prinz et al. 2006), and chronic pain (Guo and Schluesener 2007; Nicotra et al. 2011; Liu et al. 2012b).

TLRs are emerging as important players in acute and chronic itch (Liu et al. 2012b). Our recent study demonstrated that TLRs, including TLR3 and TLR7, are expressed by a subset of primary sensory neurons, which coexpress itch signaling components such as transient receptor potential vanilloid subtype 1 (TRPV1) (Liu et al. 2010, 2012a), and play an important role in itch sensation. TLRs are considered as cellular sensors for detecting exogenous and endogenous ligands/agonists in primary sensory neurons to initiate itch sensation associated with skin infection and tissue injury.