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Jon D Levine - One of the best experts on this subject based on the ideXlab platform.

  • in vitro Nociceptor neuroplasticity associated with in vivo opioid induced hyperalgesia
    The Journal of Neuroscience, 2019
    Co-Authors: Eugen V Khomula, Dioneia Araldi, Jon D Levine
    Abstract:

    Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of Nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in Nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral Nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, two days after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting Nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a mu-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4-positive and IB4-negative neurons. This sensitizing effect of fentanyl was reversed in weakly IB4-positive DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces Nociceptor neuroplasticity, which persists in culture, providing evidence for the role of Nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of Nociceptors, in OIH. SIGNIFICANCE STATEMENT Clinically used mu-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an in vitro model of Nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming, induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured Nociceptors from opioid naive and opioid primed animals, and provide evidence for the important role of Nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of Nociceptors, in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.

  • role of Nociceptor toll like receptor 4 tlr4 in opioid induced hyperalgesia and hyperalgesic priming
    The Journal of Neuroscience, 2019
    Co-Authors: Dioneia Araldi, Oliver Bogen, Paul G. Green, Jon D Levine
    Abstract:

    In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar Nociceptor mechanisms. In male rats, we first evaluated the role of Nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E2 hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C e (PKCe) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4+ and peptidergic Nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCe, HDM-induced analgesia, and priming are neither TLR4 nor PKCe dependent. OIH produced by LDM is mediated by both IB4+ and peptidergic Nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4+ and peptidergic Nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.SIGNIFICANCE STATEMENT Opioid-induced hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C e (PKCe) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCe dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4+) and peptidergic Nociceptors, whereas priming is dependent on a different class of Nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4+ and peptidergic Nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.

  • fentanyl induces rapid onset hyperalgesic priming type i at peripheral and type ii at central Nociceptor terminals
    The Journal of Neuroscience, 2018
    Co-Authors: Dioneia Araldi, Eugen V Khomula, Luiz F Ferrari, Jon D Levine
    Abstract:

    Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in Nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both Nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor. Mu-opioid receptor (MOR) antisense prevented fentanyl hyperalgesia and priming. To determine whether type I and II priming occur in the same population of neurons, we used isolectin B4-saporin or [Sar9, Met(O2)11]-substance P-saporin to deplete nonpeptidergic or peptidergic Nociceptors, respectively. Following intrathecal fentanyl, central terminal priming was prevented by both saporins, whereas that in peripheral terminal was not attenuated even by their combination. However, after intradermal fentanyl, priming in the peripheral terminal requires both peptidergic and nonpeptidergic Nociceptors, whereas that in the central terminal is dependent only on peptidergic Nociceptors. Pretreatment with dantrolene at either terminal prevented fentanyl-induced priming in both terminals, suggesting communication between central and peripheral terminals mediated by intracellular Ca2+ signaling. In vitro application of fentanyl increased cytoplasmic Ca2+ concentration in dorsal root ganglion neurons, which was prevented by pretreatment with dantrolene and naloxone. Therefore, acting at MOR in the Nociceptor, fentanyl induces hyperalgesia and priming rapidly at both the central (type II) and peripheral (type I) terminal and this is mediated by Ca2+ signaling.SIGNIFICANCE STATEMENT Fentanyl, acting at the μ-opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of Nociceptors and this is mediated by endoplasmic reticulum Ca2+ signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain.

  • repeated mu opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain
    The Journal of Neuroscience, 2015
    Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D Levine
    Abstract:

    The primary afferent Nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Ce (PKCe), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCe, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive Nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the Nociceptor. SIGNIFICANCE STATEMENT The current study demonstrates the molecular mechanisms involved in the sensitization of Nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.

  • gdnf induces mechanical hyperalgesia in muscle by reducing ibk in isolectin b4 positive Nociceptors
    Neuroscience, 2012
    Co-Authors: Jan Hendrich, Xiaojie Chen, Pedro Alvarez, Jon D Levine
    Abstract:

    We have assessed the mechanism underlying glial cell-derived neurotrophic factor (GDNF)-induced mechanical hyperalgesia in the gastrocnemius muscle, using patch clamp electrophysiology, in vivo electrophysiology and behavioral studies. Cultured isolectin B4-positive (IB4+) dorsal root ganglion neurons that innervated this muscle were held under current clamp; the majority developed an increase in action potential duration (a factor of increase of 2.29 ± 0.24, compared to 1.13 ± 0.17 in control, P < 0.01) in response to GDNF (200 ng/ml) by 15 min after application. They also demonstrated a depolarization of resting membrane potential, but without significant changes in rheobase, action potential peak, or after-hyperpolarization. Large-conductance voltage- and calcium-activated potassium (BK) channels, which have recently been shown to play a role in the repolarization of IB4+ Nociceptors, were inhibited under voltage clamp, as indicated by a significant reduction in the iberiotoxin-sensitive current. In vivo single-fiber recording from muscle afferents revealed that injection of iberiotoxin into their peripheral nociceptive field caused an increase in Nociceptor firing in response to a 60 s suprathreshold stimulus (an increase from 392.2 ± 119.8 spikes to 596.1 ± 170.8 spikes, P < 0.05). This was observed in the absence of changes in the mechanical threshold. Finally, injection of iberiotoxin into the gastrocnemius muscle produced dose-dependent mechanical hyperalgesia. These data support the suggestion that GDNF induces Nociceptor sensitization and mechanical hyperalgesia, at least in part, by inhibiting BK current in IB4+ Nociceptors.

Thomas E Taylorclark - One of the best experts on this subject based on the ideXlab platform.

  • antimycin a induced mitochondrial dysfunction activates vagal sensory neurons via ros dependent activation of trpa1 and ros independent activation of trpv1
    Brain Research, 2019
    Co-Authors: Katherine R Stanford, Stephen H Hadley, Parmvir K Bahia, Ivan Barannikov, Joanne M Ajmo, Thomas E Taylorclark
    Abstract:

    Abstract Inflammation causes activation of nociceptive sensory nerves, resulting in debilitating sensations and reflexes. Inflammation also induces mitochondrial dysfunction through multiple mechanisms. Sensory nerve terminals are densely packed with mitochondria, suggesting that mitochondrial signaling may play a role in inflammation-induced nociception. We have previously shown that agents that induce mitochondrial dysfunction, such as antimycin A, activate a subset of nociceptive vagal sensory nerves that express transient receptor potential (TRP) channels ankyrin 1 (A1) and vanilloid 1 (V1). However, the mechanisms underlying these responses are incompletely understood. Here, we studied the contribution of TRPA1, TRPV1 and reactive oxygen species (ROS) to antimycin A-induced vagal sensory nerve activation in dissociated neurons and at the sensory terminals of bronchopulmonary C-fibers. Nociceptive neurons were defined chemically and genetically. Antimycin A-evoked activation of vagal Nociceptors in a Fura2 Ca2+ assay correlated with TRPV1 responses compared to TRPA1 responses. Nociceptor activation was dependent on both TRP channels, with TRPV1 predominating in a majority of responding Nociceptors and TRPA1 predominating only in Nociceptors with the greatest responses. Surprisingly, both TRPA1 and TRPV1 were activated by H2O2 when expressed in HEK293. Nevertheless, targeting ROS had no effect of antimycin A-evoked TRPV1 activation in either HEK293 or vagal neurons. In contrast, targeting ROS inhibited antimycin A-evoked TRPA1 activation in HEK293, vagal neurons and bronchopulmonary C-fibers, and a ROS-insensitive TRPA1 mutant was completely insensitive to antimycin A. We therefore conclude that mitochondrial dysfunction activates vagal Nociceptors by ROS-dependent (TRPA1) and ROS-independent (TRPV1) mechanisms.

  • sensory nerve terminal mitochondrial dysfunction induces hyperexcitability in airway Nociceptors via protein kinase c
    Molecular Pharmacology, 2014
    Co-Authors: Stephen H Hadley, Parmvir K Bahia, Thomas E Taylorclark
    Abstract:

    Airway sensory nerve excitability is a key determinant of respiratory disease-associated reflexes and sensations such as cough and dyspnea. Inflammatory signaling modulates mitochondrial function and produces reactive oxygen species (ROS). Peripheral terminals of sensory nerves are densely packed with mitochondria; thus, we hypothesized that mitochondrial modulation would alter neuronal excitability. We recorded action potential firing from the terminals of individual bronchopulmonary C-fibers using a mouse ex vivo lung-vagal ganglia preparation. C-fibers were characterized as Nociceptors or non-Nociceptors based upon conduction velocity and response to transient receptor potential (TRP) channel agonists. Antimycin A (mitochondrial complex III Qi site inhibitor) had no effect on the excitability of non-Nociceptors. However, antimycin A increased excitability in nociceptive C-fibers, decreasing the mechanical threshold by 50% and increasing the action potential firing elicited by a P2X2/3 agonist to 270% of control. Antimycin A–induced Nociceptor hyperexcitability was independent of TRP ankyrin 1 or TRP vanilloid 1 channels. Blocking mitochondrial ATP production with oligomycin or myxothiazol had no effect on excitability. Antimycin A–induced hyperexcitability was dependent on mitochondrial ROS and was blocked by intracellular antioxidants. ROS are known to activate protein kinase C (PKC). Antimycin A–induced hyperexcitability was inhibited by the PKC inhibitor bisindolylmaleimide (BIM) I, but not by its inactive analog BIM V. In dissociated vagal neurons, antimycin A caused ROS-dependent PKC translocation to the membrane. Finally, H2O2 also induced PKC-dependent nociceptive C-fiber hyperexcitability and PKC translocation. In conclusion, ROS evoked by mitochondrial dysfunction caused Nociceptor hyperexcitability via the translocation and activation of PKC.

Sally N. Lawson - One of the best experts on this subject based on the ideXlab platform.

  • Nociceptor subtypes and their incidence in rat lumbar dorsal root ganglia (DRGs): focussing on C-polymodal Nociceptors, Aβ-Nociceptors, moderate pressure receptors and their receptive field depths
    Current Opinion in Physiology, 2019
    Co-Authors: Sally N. Lawson, Xin Fang, Laiche Djouhri
    Abstract:

    A recent study with Ca++-sensitive-dyes in neurons in whole DRGs (Table 5) found that much lower percentages of Nociceptors were polymodal-Nociceptors (PMNs) (Emery et al., 2016), than the 50–80% values in many electrophysiological fiber studies. This conflict highlighted the lack of knowledge about percentages of Nociceptor-subtypes in the DRG. This was analysed from intracellularly-recorded neurons in rat lumbar DRGs stimulated from outside the skin. Polymodal Nociceptors (PMNs) were 11% of all neurons and 19% of all Nociceptors. Most PMNs had C-fibers (CPMNs). Percentages of C-Nociceptors that were CPMNs varied with receptive field (RF) depths, whether superficial (∼80%), dermal (25%), deep (0%) or cutaneous (superficial + dermal) (40%). This explains CPMN percentages 40–90%, being highest, in electrophysiological studies using cutaneous nerves, and lowest in studies that also include deep RFs, including ours, and the recent Ca++-imaging studies in whole DRGs. Despite having been originally described in 1967 (Burgess and Perl), both Aβ-Nociceptors and Aβ-moderate pressure receptors (MPRs) remain overlooked. Most A-fiber Nociceptors in rodents have Aβ-fibers. Of rat lumbar Aβ-Nociceptors with superficial RFs, 50% were MPRs with variable medium-low trkA-expression. Despite having conduction velocities at the two extremes for Nociceptors, both CPMNs and MPRs have relatively low thresholds, superficial/epidermal RFs and low trkA-expression. For abbreviations used see Table 5 .

  • intense isolectin b4 binding in rat dorsal root ganglion neurons distinguishes c fiber Nociceptors with broad action potentials and high nav1 9 expression
    The Journal of Neuroscience, 2006
    Co-Authors: Xin Fang, Laiche Djouhri, Simon Mcmullan, Carol Berry, Kenji Okuse, Stephen G Waxman, Sally N. Lawson
    Abstract:

    Binding to isolectin-B4 (IB4) and expression of tyrosine kinase A (trkA) (the high-affinity NGF receptor) have been used to define two different subgroups of nociceptive small dorsal root ganglion (DRG) neurons. We previously showed that only Nociceptors have high trkA levels. However, information about sensory and electrophysiological properties in vivo of single identified IB4-binding neurons, and about their trkA expression levels, is lacking. IB4-positive (IB4+) and small dark neurons had similar size distributions. We examined IB4-binding levels in >120 dye-injected DRG neurons with sensory and electrophysiological properties recorded in vivo. Relative immunointensities for trkA and two TTX-resistant sodium channels (Nav1.8 and Nav1.9) were also measured in these neurons. IB4+ neurons were classified as strongly or weakly IB4+. All strongly IB4+ neurons were C-Nociceptor type (C-fiber nociceptive or unresponsive). Of 32 C-Nociceptor-type neurons examined, ~50% were strongly IB4+, ~20% were weakly IB4+ and ~30% were IB4–. A{delta} low-threshold mechanoreceptive (LTM) neurons were weakly IB4+ or IB4–. All 33 A-fiber Nociceptors and all 44 A{alpha}/beta-LTM neurons examined were IB4–. IB4+ compared with IB4– C-Nociceptor-type neurons had longer somatic action potential durations and rise times, slower conduction velocities, more negative membrane potentials, and greater immunointensities for Nav1.9 but not Nav1.8. Immunointensities of IB4 binding in C-neurons were positively correlated with those of Nav1.9 but not Nav1.8. Of 23 C-neurons tested for both trkA and IB4, ~35% were trkA+/IB4+ but with negatively correlated immunointensities; 26% were IB4+/trkA–, and 35% were IB4–/trkA+. We conclude that strongly IB4+ DRG neurons are exclusively C-Nociceptor type and that high Nav1.9 expression may contribute to their distinct membrane properties.

  • spontaneous pain both neuropathic and inflammatory is related to frequency of spontaneous firing in intact c fiber Nociceptors
    The Journal of Neuroscience, 2006
    Co-Authors: Laiche Djouhri, Simon Mcmullan, Xin Fang, Stella Koutsikou, Sally N. Lawson
    Abstract:

    Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL). To determine whether SFL is caused by spontaneous firing in nociceptive neurons, we studied the following groups of rats: (1) untreated; (2) spinal nerve axotomy (SNA), L5 SNA 1 week earlier; (3) mSNA (modified SNA), SNA plus loose ligation of the adjacent L4 spinal nerve with inflammation-inducing chromic gut; and (4) CFA (complete Freund’s adjuvant), intradermal complete Freund’s adjuvant-induced hindlimb inflammation 1 and 4 d earlier. In all groups, recordings of SFL and of spontaneous activity (SA) in ipsilateral dorsal root ganglion (DRG) neurons (intracellularly) were made. Evoked pain behaviors were measured in nerve injury (SNA/mSNA) groups. Percentages of nociceptive-type C-fiber neurons (C-Nociceptors) with SA increased in intact L4 but not axotomized L5 DRGs in SNA and mSNA (to 35%), and in L4/L5 DRGs 1–4 d after CFA (to 38–25%). SFL occurred in mSNA but not SNA rats. It was not correlated with mechanical allodynia, extent of L4 fiber damage [ATF3 (activation transcription factor 3) immunostaining], or percentage of L4 C-Nociceptors with SA. However, L4 C-Nociceptors with SA fired faster after mSNA (1.8 Hz) than SNA (0.02 Hz); estimated L4 total firing rates were ∼5.0 and ∼0.6 kHz, respectively. Similarly, after CFA, faster L4 C-Nociceptor SA after 1 d was associated with SFL, whereas slower SA after 4 d was not. Thus, inflammation causes L4 C-Nociceptor SA and SFL. Overall, SFL was related to SA rate in intact C-Nociceptors. Both L5 degeneration and chromic gut cause inflammation. Therefore, both SA and SFL/spontaneous pain after nerve injury (mSNA) may result from cumulative neuroinflammation.

Philipp Starkl - One of the best experts on this subject based on the ideXlab platform.

  • house dust mites activate Nociceptor mast cell clusters to drive type 2 skin inflammation
    Nature Immunology, 2019
    Co-Authors: Nadine Serhan, Lilian Basso, Riccardo Sibilano, Camille Petitfils, James Meixiong, Chrystelle Bonnart, Laurent L Reber, Thomas Marichal, Philipp Starkl
    Abstract:

    Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic Nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated Nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such Nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ Nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

  • house dust mites activate Nociceptor mast cell clusters to drive type 2 skin inflammation
    Nature Immunology, 2019
    Co-Authors: Nadine Serhan, Lilian Basso, Riccardo Sibilano, Camille Petitfils, James Meixiong, Chrystelle Bonnart, Laurent L Reber, Thomas Marichal, Philipp Starkl
    Abstract:

    Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic Nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated Nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such Nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ Nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions. Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1+ sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.

Laurent L Reber - One of the best experts on this subject based on the ideXlab platform.

  • house dust mites activate Nociceptor mast cell clusters to drive type 2 skin inflammation
    Nature Immunology, 2019
    Co-Authors: Nadine Serhan, Lilian Basso, Riccardo Sibilano, Camille Petitfils, James Meixiong, Chrystelle Bonnart, Laurent L Reber, Thomas Marichal, Philipp Starkl
    Abstract:

    Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic Nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated Nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such Nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ Nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

  • house dust mites activate Nociceptor mast cell clusters to drive type 2 skin inflammation
    Nature Immunology, 2019
    Co-Authors: Nadine Serhan, Lilian Basso, Riccardo Sibilano, Camille Petitfils, James Meixiong, Chrystelle Bonnart, Laurent L Reber, Thomas Marichal, Philipp Starkl
    Abstract:

    Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic Nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated Nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such Nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ Nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions. Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1+ sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.