Allergic Itch Research Articles

MrgprA3+ Primary Sensory Neurons Mediate Acute Allergic Itch Responses in Atopic Dermatitis Model Mice.

Itch is a prominent symptom of atopic dermatitis (AD). However, the underlying mechanism remains complex and has not yet been fully elucidated. Mas-related G protein-coupled receptor A3 (MrgprA3) has emerged attention as a marker of primary sensory neurons that specifically transmit itch signals; however, its involvement in AD-related itch has not been extensively explored. In this study, we developed an AD itch mouse model by repeatedly applying house dust mite (HDM) extract to barrier-impaired skin via a special diet. To clarify the role of MrgprA3+ neurons in itch behavior in our AD model, we adopted a toxin receptor-mediated cell knockout strategy using transgenic mice in which the diphtheria toxin receptor (DTR) gene was placed under the control of the Mrgpra3 promoter. When the HDM extract was repeatedly applied to the face and back skin of special diet-fed mice, the mice exhibited AD-like dry and eczematous skin lesions accompanied by three types of itch-related behaviors:1) spontaneous scratching, 2) acute scratching after antigen challenge, and 3) light touch-evoked scratching. Upon diphtheria toxin administration, substantial depletion of DTR+/MrgprA3+ neurons was observed in the dorsal root ganglion. Ablation of MrgprA3+ neurons suppressed acute itch responses after HDM application, whereas spontaneous and touch-evoked itch behaviors remained unaffected. Our findings unequivocally demonstrate that in our AD model, MrgprA3+ primary sensory neurons mediate acute allergic itch responses, whereas these neurons are not involved in spontaneous itch or alloknesis.

377 Potentiation of mast cell-mediated allergic itch by IL-33

377 Potentiation of mast cell-mediated allergic itch by IL-33

Neuronal Fc\u03b5RI\u03b1 directly mediates ocular itch via IgE-immune complex in a mouse model of allergic conjunctivitis

BackgroundClassical understanding of allergic conjunctivitis (ACJ) suggests that ocular itch results from a mast cell-dependent inflammatory process. However, treatments that target inflammatory mediators or immune cells are often unsatisfying in relieving the stubborn itch symptom. This suggests that additional mechanisms are responsible for ocular itch in ACJ. In this study, we aim to determine the role of neuronal FcεRIa in allergic ocular itch.MethodsCalcium imaging was applied to observe the effect of IgE-immune complex in trigeminal neurons. Genomic FcεRIa knockout mice and adeno-associated virus (AAV) mediated sensory neuron FcεRIa knockdown mice were used in conjunction with behavioral tests to determine ocular itch. In addition, immunohistochemistry, Western blot and quantitative RT-PCR were used for in vitro experiments.ResultsWe found that FcεRIα was expressed in a subpopulation of conjunctiva sensory neurons. IgE-IC directly activated trigeminal neurons and evoked acute ocular itch without detectible conjunctival inflammation. These effects were attenuated in both a global FcεRIa-knockout mice and after sensory neuronal-specific FcεRIa-knockdown in the mouse trigeminal ganglion. In an ovalbumin (OVA) induced murine ACJ model, FcεRIα was found upregulated in conjunctiva-innervating CGRP+ sensory neurons. Sensory neuronal-specific knockdown of FcεRIa significantly alleviated ocular itch in the ACJ mice without affecting the immune cell infiltration and mast cell activation in conjunctiva. Although FcεRIα mRNA expression was not increased by IgE in dissociated trigeminal ganglion neurons, FcεRIα protein level was enhanced by IgE in a cycloheximide-resistance manner, with concordant enhancement of neuronal responses to IgE-IC. In addition, incremental sensitization gradually enhanced the expression of FcεRIα in small-sized trigeminal neurons and aggravated OVA induced ocular itch.ConclusionsOur study demonstrates that FcεRIα in pruriceptive neurons directly mediates IgE-IC evoked itch and plays an important role in ocular itch in a mouse model of ACJ. These findings reveal another axis of neuroimmune interaction in allergic itch condition independent to the classical IgE-mast cell pathway, and might suggest novel therapeutic strategies for the treatment of pruritus in ACJ and other immune-related disorders.

The emerging role of neuroimmune interactions in atopic dermatitis and itch

Millions of people globally suffer from allergic diseases, and the cases have been rising in the past decades. One of the major manifestations of allergic diseases is itch, which is an unpleasant symptom that triggers the urge to scratch and greatly affects the quality of life. Thus, research on how sensation of itch is detected/transmitted from the contact of the allergen to the nervous system is crucial in mitigating itch. Recent studies have attempted to elucidate the mechanisms of itch in allergic diseases. Here, we aim to review the endogenous mediators released from immune/nonimmune skin cells (that are indirectly involved in the propagation of itch) and the sensory neurons that express receptors for these itch mediators that are associated with direct transmission of itch in cutaneous allergic diseases. As the mechanisms for allergic itch become clearer, new therapeutic approaches to relieve itch are likely to be developed. Recent clinical trials are testing numerous compounds that target the endogenous mediators and their receptors. These studies provide the possibility of more effective itch treatment for allergic diseases.

Song, and: Connecticut, and: My Brother Does Not Return for My Mother’s Fiftieth

Song, and: Connecticut, and: My Brother Does Not Return for My Mother’s Fiftieth Tawanda Mulalu (bio) Song Forgive myself for breath and I should die.Self-love an excuse but for that exit: this daydreamof me ended. Of feet parched with weight beyondthe hurt of pale bathroom scale. Or love thisitch between thighs as slower metabolism giftsslower moods, these dull penetrations of faceinto pillowcase. So die then, says another countryor lover; splits me long through thoughts of this spine.And a dream of nerve cells copying beneath this glass.How inexact to possess skin. Like a flailing sacktoo stuffed with consciousness. I feel as a piñataand you are peckish. Not just the promise of guns shotbut allergic itch draws blood in late summer. I’m sorryother Black men died. I’m sorry I keep thinking,I look like him. I’m sorry my life feels as easyas these leaves failing to defend themselves againsttheir too-soon shifting colors. But I want myself.I want to want myself as much as I want your shadowsflickering against the walls of this cave, fooling meof presences beyond myself. And this music: I want thisfoolishness of my mouth transmuted into woodwindand brass. As if this could salve. As if this grass betweenmy lips epistles this gray sky as any virtue but failed rain.As if peaches. Forgive myself for breath and this songshould die. I am as new as the paintings in this cave.Am the same burrowing of grain into body and loss.Am the same ochre and hematite, inevitable and sorry. [End Page 18] Connecticut Mornings, his wife could not remember who my face was.Her face stared at me with a mushy smile while Henry ate the same corn flakes with bananas. I watched the yellow flakesuncrisping in his bowl of milk, his gums too soft to bear them. Henry then put me to work on his “fields.” I don’t know whofirst said it. Probably, his teeth cackled “fields” to his friend who visited him—limping gently—as Henry rolled around in hisred tractor. It roared through his backyard, funneling narrow lanes into the black, hot soil. Waddling after him in my white sneakers,I held blue seeds of grass that pricked my fingers. I tossed them over the soil like a flower girl. “Why are they blue?” I asked him.“Fertilizer coating,” he said. “Dry, mutant rice,” said my fizzy mind. Nights—they opened with heavy sweat—he would sit and watchFox News blare. Me next to him, reading a long novel on suffering. But he shouldn’t have paid me as a gardener. I dug about as wellas a child in a sandbox—shallow, amazed by my skinny handling of that spade. Its crusted rust as dark as my dry skin. No, Henry paidmy hands to hold his loneliness. To hear him. I needed a place to stay. He liked to hear me singing off-key in the mornings, taking longcold showers. And walk down these stairs to him: aging, waiting to plant more blue seeds. [End Page 19] My Brother Does Not Return for My Mother’s Fiftieth Egg that could but did not quite, I see you in theirmuseums, the coal-dark African masks, your blank face. To not find you walking with me with thesestolen faces, to not find you crawling up from dust— I left you landlocked with our parents, heard tidesbefore my body, wet axes carving shore to noise, and who has ever rescued the drive home? Washedmy crusted hands and what—stubborn grains. Dried my hands with a cold towel, your little hands driedbut could not hold their shores—though other grains now live between your fingers. This world will nothold little hands but turned to dust. At this party, I sip on bitter-dark drink, bearing warm speecheswhile your body turns to airlessness. My thoughts on this glass, roundedness of your once new skullI never saw. My flight returns to their shores. Your face escapes me...

Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

SUMMARYChronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αVβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αVβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch.

The Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

Chronic allergic itch is a major symptom that affects millions of people and animals, but its pathogenesis is not fully explained. Here, we show that one of the mediators abundantly present in the skin of patients with atopic dermatitis, periostin, induces itch via sensory neurons in mice, dogs, and monkeys. We identified the periostin receptor, the integrin αvβ3 expressed on a subset of sensory neurons. Using pharmacological and genetic approaches, we inhibited the function of this neuronal integrin αvβ3, which significantly reduced periostin-mediated itch in mice. Furthermore, we showed that the cytokine TSLP, and the application of the AD-causing MC903 (calcipotriol) and house dust mites induced periostin secretion. Finally, we established that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Overall, our results identified a TSLP-periostin reciprocal activation that links the skin to the central nervous system via peripheral sensory neurons, and we characterized the non-canonical functional role of a neuronal integrin in itch behavior.

Peripheral gabapentin regulates mosquito allergy-induced itch in mice

The antipruritic activity of gabapentin, an anticonvulsant, was studied in a mouse model of allergic itch. In mice sensitized by an extract of the salivary glands of the mosquito (ESGM), an intradermal injection of ESGM elicited scratching and increased peripheral nerve firing. Oral or intradermal administration of gabapentin at the ESGM injection site inhibited ESGM-induced scratching and peripheral nerve firing. However, gabapentin did not affect histamine-induced scratching. The distributions of immunoreactivity to the voltage-dependent calcium channel α2δ-1 subunit, a site of gabapentin action, and the histamine H1 receptor differed in the mouse dorsal root ganglia. The α2δ-1 subunit was mainly found in neurons that were 15–20 µm in diameter, whereas the H1 receptor was mainly in 20–30 µm neurons. In addition, α2δ-1 subunit immunoreactivity co-localized with that of transient receptor potential vanilloid 1 (TRPV1). These results suggest that gabapentin regulates allergic itch by acting on the calcium channel α2δ-1 subunit in peripheral TRPV1-positive neurons.

Mrgprs activation is required for chronic itch conditions in mice.

Chronic itch has been drawing much attention due to its clinical significance and the complexity of its mechanisms. To facilitate the development of anti-itch strategies, it is necessary to investigate the key players in itch sensation under chronic itch conditions. Several members of the Mrgpr family were identified as itch receptors that detect cutaneous pruritogens in primary sensory neurons. However, the role of Mrgprs in chronic itch conditions has not been well described. Scratching behaviors of WT and Mrgpr-clusterΔ-/- mice were examined in dry skin model and contact dermatitis model to examine the role of Mrgpr genes in mediating chronic itch sensation. Scratching behaviors of the mice were also examined in allergic itch model. Real-time PCR were performed to examine the expression level of MrgprA3 and MrgprC11 under naïve and dry skin conditions. The MrgprA3+ itch-sensing fibers were labeled by tdTomato fluorescence in Mrgpra3GFP-Cre; ROSA26tdTomato mice, and the morphology and density of those fibers in the epidermis were analyzed under dry skin condition. We showed that deleting a cluster of Mrgpr genes in mice reduced scratching behavior severely under two chronic itch conditions, namely dry skin and contact dermatitis, and the allergic itch condition. Moreover, the gene expressions of itch receptors MrgprA3 and MrgprC11 in dorsal root ganglia (DRG) were upregulated significantly under dry skin condition. Consistently, the percentage of MrgprA3+ itch-sensing neurons was increased as well. We also observed hyperinnervation of MrgprA3+ itch-sensing fibers in the epidermis of the skin under dry skin condition. We demonstrate that Mrgprs play important roles in mediating chronic itch and allergic itch. These findings enrich our knowledge of itch mechanism and may lead to the development of novel therapeutic approach to combat itch.

Cl- channel is required for CXCL10-induced neuronal activation and itch response in a murine model of allergic contact dermatitis.

Persistent itch often accompanies allergic contact dermatitis (ACD), but the underlying mechanisms remain largely unexplored. We previously demonstrated that CXCL10/CXCR3 signaling activated a subpopulation of cutaneous primary sensory neurons and mediated itch response after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. The purpose of this study was to determine the ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch. In whole cell recordings, CXCL10 triggered a current in dorsal root ganglion (DRG) neurons innervating the area of CHS. This current was modulated by intracellular Cl- and blocked by the general Cl- channel inhibitors. Moreover, increasing Ca2+ buffering capacity reduced this current. In addition, blockade of Cl- channels significantly suppressed CXCL10-induced Ca2+ response. In behavioral tests, injection of CXCL10 into CHS site exacerbated itch-related scratching behaviors. Moreover, the potentiating behavioral effects of CXCL10 were attenuated by either of two Cl- channel blockers. Thus we suggest that the Cl- channel acts as a downstream target mediating the excitatory and pruritic behavioral effects of CXCL10. Cl- channels may provide a promising therapeutic target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.NEW & NOTEWORTHY The ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch are largely unexplored. This study revealed that CXCL10 evoked an ionic current mainly carried by Cl- channels. We suggest that Cl- channels are likely key molecular candidates responsible for the CXCL10-evoked neuronal activation and itch-like behaviors in a murine model of allergic contact dermatitis induced by the antigen squaric acid dibutylester. Cl- channels may emerge as a promising drug target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.

A histamine-independent itch pathway is required for allergic ocular itch

Non-histaminergic TRPA1 neural pathway is required for the development of allergic ocular itch. Pharmacological inhibition of TRPA1 channel can lead to novel therapeutic strategies to treat ocular itch in severe allergic conjunctivitis.

CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis.

Persistent itch is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is predominantly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of ACD, it is largely unexplored for itch and pain accompanying this disorder. Here, we showed that CXCL10 and CXCR3 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activated a subset of cutaneous dorsal root ganglion neurons innervating the area of CHS through neuronal CXCR3. In behavioral tests, a CXCR3 antagonist attenuated spontaneous itch- but not pain-like behaviors directed to the site of CHS. Injection of CXCL10 into the site of CHS elicited site-directed itch- but not pain-like behaviors, but neither type of CXCL10-evoked behaviors was observed in control mice. These results suggest that CXCL10/CXCR3 signaling mediates allergic itch but not inflammatory pain in the context of skin inflammation. Thus, upregulation of CXCL10/CXCR3 signaling in sensory neurons may contribute to itch associated with ACD. Targeting the CXCL10/CXCR3 signaling might be beneficial for the treatment of allergic itch.

Atopic itch in dogs: pharmacology and modeling.

Itch is the most common clinical problem seen in dogs with skin diseases. Although an etiological classification of canine pruritus does not yet exist, most causes would likely fall into the IFSI class I (dermatological) itch. One of the most common causes of canine itch is that associated with atopic dermatitis, and there is randomized controlled trial grade evidence of the efficacy of several antipruritic interventions. At this time, the mainstay of treatment of canine atopic itch relies principally on the use of topical and/or oral glucocorticoids and oral cyclosporine. Type 1 receptor antihistamines are notorious in their inconsistency in reducing pruritus in atopic dogs. A new Janus kinase (JAK)-1 inhibitor has recently been approved for treatment of allergic itch in dogs, and its onset of efficacy is remarkably fast. Modeling itch in dogs can be achieved by allergen sensitization (fleas, house dust mites), and challenges that elicit pruritic manifestation can be used for mechanistic studies as well as for testing of novel anti-itch modalities.

The role of heat in rubbing and massage-related corneal deformation

To examine the role of elevated corneal temperature in the development of rubbing/massage-related corneal deformation and the possibility that warm compresses in the management of meibomian gland dysfunction or chalazion could contribute to such adverse responses. With reference to reports of corneal deformation associated with meibomian gland dysfunction, chalazion, dacryocystoceles and post-trabeculectomy, the mechanisms for increased corneal temperature due to ocular massage, especially when combined with warm compresses are examined. Several mechanisms for rubbing/massage to elevate corneal temperature have been described, apart from the application of warm compresses or other forms of heat. Raised corneal temperature helps to explain corneal deformation which develops in association with rubbing or massage in conditions such as keratoconus, chalazion, post-trabeculectomy, post-laser assisted in situ keratomileusis, post-graft and dacryocystoceles. When combined with warm compresses or other methods of heat delivery to the eye, the elevation of corneal temperature appears to explain how meibomian gland dysfunction treatment involving warm compresses and massage could induce rubbing-related deformation. Patients whose management involves iatrogenic ocular massage appear to require screening for risk of corneal deformation. Risk may be increased for patients with a concurrent habit of rubbing their eyes abnormally in response to allergic itch for example. It appears to be possible to modify ocular massage techniques to reduce the risk of corneal deformation. Careful tutoring and follow-up using corneal topography appears to be required when massage is prescribed, especially when used in conjunction with heat application.

Tonic Inhibition of Allergic Itch Signaling by the Descending Noradrenergic System in Mice

We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elicited biting, an itch-related response, in sensitized mice. The biting was inhibited by intrathecal clonidine and reversed by yohimbine, an α2-adrenoceptor antagonist. The biting was increased by intrathecal pretreatment with the catecholaminergic neurotoxin 6-hydroxydopamine and the α-adrenoceptor antagonist phentolamine but not the serotonergic neurotoxin 5,7-dihydroxytryptamine. We propose that α2-adrenoceptors are involved in the inhibition of allergic itch in the spinal cord and that the descending noradrenergic system exerts a tonic inhibition on the itch signaling. The serotonergic system may not be involved.

Inhibitory Effects of the Methanol Extract of Ganoderma lucidum on Mosquito Allergy–Induced Itch-Associated Responses in Mice

Recently, we showed that a methanol extract of Ganoderma lucidum inhibits scratching, an itch-related response, induced by intradermal injections of some pruritogens in mice. The present study investigated whether G. lucidum extract would inhibit allergic itch. In mice sensitized with an extract of salivary gland of mosquito (ESGM), an intradermal injection of ESGM elicited scratching, which was suppressed by oral administration of G. lucidum extract (100 and 300 mg/kg). The scratching was inhibited by the H₁ histamine-receptor antagonist azelastine, but not by the peripherally acting H₁-antagonist terfenadine, at the oral dose of 30 mg/kg. In sensitized mice, ESGM increased the activity of cutaneous nerve, which was suppressed by G. lucidum extract (300 mg/kg). Although terfenadine (30 mg/kg) inhibited plasma extravasation induced by ESGM in the sensitized mice, G. lucidum extract (300 mg/kg) was without effect. These results suggest that G. lucidum extract relieves allergic itch through a peripheral action. The results support the idea that mast cells and H₁ histamine receptors are not the primary sites of the antipruritic action of G. lucidum extract.

Itch-related responses of dorsal horn neurons to cutaneous allergic stimulation in mice

This study was conducted to identify the mechanosensitive dorsal horn neurons involved in allergic itch. We examined 98 units responsive to cutaneous allergy; 90 showed only immediate responses, which subsided before the onset of itch-related behavior and eight showed immediate and sustained responses, the latter of which was similar in duration to itch-related behavior, suggesting the involvement of sustained units in itch signaling. Sustained units were localized in the superficial, but not deep, layers of the dorsal horn. They were wide dynamic range or nociceptive specific, but not low threshold and four of eight were noxious heat sensitive. The results suggest that a small minority of neurons in the superficial dorsal horn are involved in allergic itch signals.

Different dorsal horn neurons responding to histamine and allergic itch stimuli

We examined whether different itch signals converge on the same dorsal horn neurons in mice. Intradermal injections of histamine and SLIGRL-NH2 (protease-activated receptor-2 agonist) induced scratching in naive mice and so did mosquito allergen in sensitized mice. These stimuli induced Fos expression in cells in the superficial dorsal horn. Fos-positive cells were mainly distributed within the isolectin B4-labeled region (inner aspect of lamina II) after histamine injection. In contrast, they were in the region dorsal to the isolectin B4-labeled region after injections of SLIGRL-NH2 and mosquito allergen. These results suggest that allergic itch signal is mediated by primary afferents expressing protease-activated receptor-2 and the neurons receiving signals of protease-associated itch and allergy-associated itch are different from those of histamine-induced itch.

Different Roles of Capsaicin-sensitive and H1 Histamine Receptor-expressing Sensory Neurones in Itch of Mosquito Allergy in Mice

Although mosquito allergy induces the release of histamine, the itch-related response, scratching, is not effectively suppressed by blockade of H1 histamine receptors. To address this question, we examined the effects of neonatal capsaicin treatment on allergic reactions and H1 histamine receptor-expressing sensory neurones in mice. Neonatal capsaicin treatment almost completely abolished allergy-associated scratching, without effects on plasma extravasation or increase in serum concentrations of immunoglobulins E and G1. An injection of edema contents from an animal exhibiting allergic reaction elicited scratching in naive animals, suggesting the production of pruritogen(s) by allergic reaction; this production was not suppressed by neonatal capsaicin treatment. This treatment markedly decreased the number of sensory neurones immunoreactive for TRPV1 capsaicin receptor, with little effect on sensory neurones immunoreactive for neurofilament 200, a marker of myelinated A-fibre neurones. In addition, there was a trend towards a reduction in numbers of sensory neurones immunoreactive for H1 histamine receptor. The results suggest that capsaicin-sensitive sensory neurones that lack H1 histamine receptors play a key role in signalling of allergic itch.