Article

Toll-like receptor 7 mediates pruritus

Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Nature Neuroscience (Impact Factor: 14.98). 10/2010; 13(12):1460-2. DOI: 10.1038/nn.2683
Source: PubMed

ABSTRACT Toll-like receptors are typically expressed in immune cells to regulate innate immunity. We found that functional Toll-like receptor 7 (TLR7) was expressed in C-fiber primary sensory neurons and was important for inducing itch (pruritus), but was not necessary for eliciting mechanical, thermal, inflammatory and neuropathic pain in mice. Our results indicate that TLR7 mediates itching and is a potential therapeutic target for anti-itch treatment in skin disease conditions.

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    • "Investigating CQ-induced scratching, which is mainly suggested as a histamine-independent response for CQ, results in further understandings about its exact mechanisms (Abila et al., 1994; Ezeamuzie et al., 1990). Previous studies have demonstrated the role of endogenous opioids (Ajayi et al., 2004; Cowan and Inan, 2009; Inan and Cowan, 2004; Onigbogi et al., 2000), gastrin-releasing peptide receptors (Liu et al., 2009), and toll-like receptor 7 in CQ-induced scratching (Liu et al., 2010). Opioids are among the mediators for CQ-induced scratching (Ajayi et al., 2004); as such, mu (μ) antagonists and kappa agonists can reverse it (Ajayi et al., 2004; Inan and Cowan, 2004). "
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    ABSTRACT: Chloroquine (CQ), a 4-aminoquinoline drug, has long been used in the treatment and prevention of malaria. However its side effect generalized pruritus contributes to treatment failures, and consequently results in the development of chloroquine resistant strains of Plasmodium falciparum. It was proposed that the administration of CQ correlated with increase in nitric oxide (NO) production. Nitric oxide is involved in some pruritic disorders such as atopic dermatitis, psoriasis and scratching behavior evoked by pruritogens like substance P. Therefore, the aim of this study was to investigate the involvement of NO/cGMP pathway in CQ-induced scratching in mice. Scratching behaviors were recorded by a camera after intradermal (ID) injection of CQ in the shaved rostral back of the mice. The results obtained show that CQ elicited scratching in a dose-dependent manner with a peak effective dose of 400 μg/site. Injection of non-specific NOS inhibitor, N-nitro-L-arginine methyl ester or neuronal NOS selective inhibitor and 7-Nitroindazole, reduced CQ-induced scratching significantly. On the other hand, administration of aminoguanidine as inducible NOS inhibitor has no inhibitory effect on this behavior. Also, injection of L-arginine as a precursor of NO significantly increased this response. Conversely, accumulation of cGMP by sildenafil as a selective phosphodiesterase type 5 inhibitor, potentiated the scratching behavior by CQ. This study therefore shows that CQ-induced scratching behavior is mediated by the NO/cGMP pathway. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology Biochemistry and Behavior 05/2015; 134. DOI:10.1016/j.pbb.2015.04.016 · 2.82 Impact Factor
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    • "In addition to MrgprA3, another marker for sensory neurons dedicated to itch is TLR7 (Toll-like receptor 7). While reporter lines for TLR7 are still lacking there is some evidence that its expression is at least partially overlapping with MrgprA3 (Liu et al., 2010). The lack of sensitivity of TLR7 knockout mice to non-histaminergeic pruritogens demonstrates that TLR7 is a direct mediator of pruritis. "
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    ABSTRACT: The word somatosensation comes from joining the Greek word for body (soma) with a word for perception (sensation). Somatosensory neurons comprise the largest sensory system in mammals and have nerve endings coursing throughout the skin, viscera, muscle, and bone. Their cell bodies reside in a chain of ganglia adjacent to the dorsal spinal cord (the dorsal root ganglia) and at the base of the skull (the trigeminal ganglia). While the neuronal cell bodies are intermingled within the ganglia, the somatosensory system is in reality composed of numerous sub-systems, each specialized to detect distinct stimuli, such as temperature and touch. Historically, somatosensory neurons have been classified using a diverse host of anatomical and physiological parameters, such as the size of the cell body, degree of myelination, histological labeling with markers, specialization of the nerve endings, projection patterns in the spinal cord and brainstem, receptive tuning, and conduction velocity of their action potentials. While useful, the picture that emerged was one of heterogeneity, with many markers at least partially overlapping. More recently, by capitalizing on advances in molecular techniques, researchers have identified specific ion channels and sensory receptors expressed in subsets of sensory neurons. These studies have proved invaluable as they allow genetic access to small subsets of neurons for further molecular dissection. Data being generated from transgenic mice favor a model whereby an array of dedicated neurons is responsible for selectively encoding different modalities. Here we review the current knowledge of the different sensory neuron subtypes in the mouse, the markers used to study them, and the neurogenetic strategies used to define their anatomical projections and functional roles.
    Frontiers in Neuroanatomy 04/2014; 8:21. DOI:10.3389/fnana.2014.00021 · 4.18 Impact Factor
    • "Recently, we have shown that TLR7 is expressed by smalldiameter DRG neurons (Liu et al., 2010) that are responsible for the sensations of pain and itch (Basbaum et al., 2009; Liu and Ji, 2013; Woolf and Ma, 2007). Furthermore, the synthetic TLR7 ligands imiquimod and loxoribine induced rapid inward currents and action potentials in DRG nociceptor neurons (Liu et al., 2010). However, the endogenous ligands of TLR7 remain to be identified. "
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    ABSTRACT: Intracellular microRNAs (miRNAs) are key regulators of gene expression. The role of extracellular miRNAs in neuronal activation and sensory behaviors are unknown. Here we report an unconventional role of extracellular miRNAs for rapid excitation of nociceptor neurons via toll-like receptor-7 (TLR7) and its coupling to TRPA1 ion channel. miRNA-let-7b induces rapid inward currents and action potentials in dorsal root ganglion (DRG) neurons. These responses require the GUUGUGU motif, only occur in neurons coexpressing TLR7 and TRPA1, and are abolished in mice lacking Tlr7 or Trpa1. Furthermore, let-7b induces TLR7/TRPA1-dependent single-channel activities in DRG neurons and HEK293 cells overexpressing TLR7/TRPA1. Intraplantar injection of let-7b elicits rapid spontaneous pain via TLR7 and TRPA1. Finally, let-7b can be released from DRG neurons by neuronal activation, and let-7b inhibitor reduces formalin-induced TRPA1 currents and spontaneous pain. Thus, secreted extracellular miRNAs may serve as novel pain mediators via activating TLR7/TRPA1 in nociceptor neurons.
    Neuron 04/2014; 82(1):47-54. DOI:10.1016/j.neuron.2014.02.011 · 15.98 Impact Factor
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