Emerging role of Toll-like receptors in the control of pain and itch

Abstract

Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors (PRRs) to initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs can also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in various cell types in the central nervous system (CNS), including non-neuronal and neuronal cells, and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, 3, and 4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of the affected people, insights into TLR signaling in nervous system will open a new avenue for the management of clinical pain and itch.

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…In 2012, we published the first special issue on mechanisms of pain and itch in Neuroscience Bulletin, which covered the peripheral, central, and glial mechanisms of pain and itch [1][2][3][4][5]. In the last 5 years, the field has seen tremendous progress in the molecular and functional characterization of primary sensory neurons [6,7], neurocircuits of pain and itch [8][9][10], immune and glial modulation of pain and itch [11][12][13][14][15], molecular mechanisms of pain [16,17], and identification of brain signatures of pain [18].…”

Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter

“…Toll-like receptors (TLRs) are traditionally expressed in immune cells to regulate innate immunity, but recent studies indicated that TLRs (such as TLR3, 4 and 7) are also expressed in primary sensory neurons, especially nociceptive neurons in dorsal root ganglia (DRGs) and trigeminal ganglia of the PNS to regulate sensory functions such as pain and itch [3][4][5][6]. TLR signaling is largely mediated by the myeloid differentiation factor 88 (MyD88) protein (but see [7]), and activation of MyD88 in turn activates the NF-κB and MAP kinase pathways, leading to the production of inflammatory cytokines and chemokines for the initiation of innate immunity [3]. Increasing evidence suggests that nociceptor neurons play a critical role in host defense and inflammation [8,9].…”

“…Taken together, our data suggest that MyD88 in nociceptive neurons maintains neuropathic pain by regulating innate and adaptive immunity in the DRG. Since nociceptive neurons also express chemokines that are critical for the trafficking of immune cells [2,3], future studies are warranted to examine whether MyD88 is involved in the expression of chemokines (e.g., CCL2, CXCL1, and CXCL10) in DRG nociceptive neurons. However, there are two potential pitfalls in this study.…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…The exogenous and endogenous ligands specific to the various TLRs have been summarized in several reviews [3,16] . Here, we are particularly interested in the endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) because they recognize nucleic acids.…”