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Toll-Like Receptors in Pain and Itch

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Neuroimmune Interactions in Pain

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Abstract

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.

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Abbreviations

AP1:

Activator Protein-1

BDNF:

Brain-Derived Neurotrophic Factor

CIPN:

Chemotherapy-Induced Peripheral Neuropathy

CLR:

C-type Lectin Receptor

CNS:

Central Nervous System

DAMP:

Damage-Associated Molecular Pattern

DRG:

Dorsal Root Ganglion

ET-1:

Endothelin-1

GPCR:

G Protein Coupled Receptor

hBD2:

Human Beta-Defensin-2

HMGB1:

High Mobility Group Box Protein 1

HSP:

Heat Shock Protein

IFM:

Inflammatory Mediator

IFN-I:

Type-I Interferon

IKK:

Inhibitor of Nuclear Factor-κB (IκB) Kinase

IL:

Interleukin

IL-1R:

Interleukin-1 Receptor-Associated Kinase (Biragyn et al. 2002)

ISG:

Interferon Stimulated Gene

LPS:

Lipopolysaccharide

LTP:

Long-Term Potentiation

MAPK:

Mitogen-Activated Protein Kinase

MyD88:

Myeloid Differentiation Primary Response 88

NF200:

Neurofilament 200

NF-κB:

Nuclear Factor-κB

NGF:

Nerve Growth Factor

NLR:

Nucleotide-Binding and Oligomerization Domain (NOD)-Like Receptor

PAMP:

Pathogen-Associated Molecular Pattern

PGE2:

Prostaglandin E2

pION:

Partial Infraorbital Nerve Ligation

PNS:

Peripheral Nervous System

Poly(I:C):

Polyinosinic-Polycytidylic Acid

PRR:

Pattern Recognition Receptor

PTX:

Paclitaxel

SDH:

Spinal Dorsal Horn

sEPSC:

Spontaneous Excitatory Postsynaptic Current

SGC:

Satellite Glial Cell

sIPSC:

Spontaneous Inhibitory Postsynaptic Current

SMOC:

Supramolecular Organizing Complex

TBK1:

Tank-Binding Kinase-1

TG:

Trigeminal Ganglion

TIR:

Toll-Interleukin-1 Receptor [Homology Domain]

TIRAP:

TIR Domain Containing Adaptor Protein

TLR:

Toll-Like receptor

TNF:

Tumor Necrosis Factor

TRAF:

TNF Receptor Associated Factor (Caterina et al. 2000)

TRIF:

TIR-Domain-Containing Adapter-Indued Interferon-Beta

TrkA:

Tropomyosin Receptor Kinase A

TRPA1:

Transient Receptor Potential Cation Channel Subfamily A Member 1

TRPM8:

Transient Receptor Potential Cation Channel Subfamily M Member 8

TRPV1:

Transient Receptor Potential Cation Channel Subfamily V Member 1

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  1. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, NC, USA

    Amanda S. Andriessen, Elmira Hezarkhani & Christopher R. Donnelly

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  1. Amanda S. Andriessen
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  2. Elmira Hezarkhani
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  3. Christopher R. Donnelly
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Correspondence to Christopher R. Donnelly .

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  1. Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA

    Ru-Rong Ji

  2. Pain Management and Neurosciences, Cleveland Clinic, Cleveland, OH, USA

    Jianguo Cheng

  3. Wellesley College, Wellesley, MA, USA

    Jasmine Ji

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Andriessen, A.S., Hezarkhani, E., Donnelly, C.R. (2023). Toll-Like Receptors in Pain and Itch. In: Ji, RR., Cheng, J., Ji, J. (eds) Neuroimmune Interactions in Pain . Springer, Cham. https://doi.org/10.1007/978-3-031-29231-6_8

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