IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Abstract

Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO₂. Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca²⁺ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.

IL-33ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

GABA(A) Receptors in the Central Nucleus of the Amygdala Are Involved in Pain- and Itch-Related Responses.

Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus

Feng-Ming Zhou1,3 • Ruo-Xiao Cheng1,3 • Shuai Wang1,2 • Ya Huang3 • Yong-Jing Gao4 • Yan Zhou3 • Teng-Teng Liu3 • Xue-Long Wang5 • Li-Hua Chen2 • Tong Liu1,3

Antioxidants Attenuate Acute and Chronic Itch Peripheral and Central Mechanisms of Oxidative Stress in Pruritus

Received: 1 July 2016 / Accepted: 27 August 2016
ⓒ Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore 2016

Abstract
Itch (pruritus) is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-α-phenylnitrone (PBN) were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetone-diethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin. Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.

Keywords

Oxidative stressAntioxidantsItchTRPA1Extracellular signal-regulated kinase
Feng-Ming Zhou and Ruo-Xiao Cheng have contributed equally to this work.

Li-Hua Chen chenlihua@suda.edu.cn
Tong Liu liutong80@suda.edu.cn
1 Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
2 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, China
3 Institute of Neuroscience, Soochow University, Suzhou 215123, China
4 Institute of Nautical Medicine, Nantong University,Nantong 226001, China
5 Beijing Electric Power Hospital, Beijing 100073, China

TRPV1 is crucial for proinflammatory STAT3 signaling and thermoregulation-associated pathways in the brain during inflammation.

supply_TRPV1 is crucial for proinflammatory STAT3 signaling and thermoregulation-associated pathways in the brain during inflammation

Fluoxetin ameliorates Atopic Dermatitis like skin lesions in BALB.c mice through reducing psychological stress and Inflammatory response

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Sara L. Morales-La ́zaro1, Itzel Llorente1, Fe ́lix Sierra-Ram ́ırez1, Ana E. Lo ́pez-Romero1, Miguel Ort ́ız-Renter ́ıa1, Barbara Serrano-Flores1, Sidney A. Simon2, Leo ́n D. Islas3 & Tamara Rosenbaum1

The transient receptor potential vanilloid 1 (TRPV1) ion channel is mainly found in primary nociceptive afferents whose activity has been linked to pathophysiological conditions including pain, itch and inflammation. Consequently, it is important to identify naturally occurring antagonists of this channel. Here we show that a naturally occurring mono- unsaturated fatty acid, oleic acid, inhibits TRPV1 activity, and also pain and itch responses in mice by interacting with the vanilloid (capsaicin)-binding pocket and promoting the stabilization of a closed state conformation. Moreover, we report an itch-inducing molecule, cyclic phosphatidic acid, that activates TRPV1 and whose pruritic activity, as well as that of histamine, occurs through the activation of this ion channel. These findings provide insights into the molecular basis of oleic acid inhibition of TRPV1 and also into a way of reducing the pathophysiological effects resulting from its activation.

1 Instituto de Fisiolog ́ıa Celular, Universidad Nacional Auto ́noma de Me ́xico, Circuito exterior s/n, Coyoacan 04510, Mexico. 2 Department of Neurobiology, Duke University, 327C Bryan Research Building, Durham, North Carolina 27710, USA. 3 Departamento de Fisiolog ́ıa, Facultad de Medicina, Universidad Nacional Auto ́noma de Me ́xico, Circuito escolar s/n, Coyoacan 04510, Mexico. Correspondence and requests for materials should be addressed to T.R. (email: trosenba@ifc.unam.mx).

Ethanol Extract of Sanguisorbae Radix Inhibits Mast Cell Degranulation and Suppresses 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions.

Involvement of TRPV1 and TDAG8 in pruriception associated with noxious acidosis.

Lin SH¹, Steinhoff M², Ikoma A³, Chang YC⁴, Cheng YR⁵, Chandra Kopparaju R⁶, Ishii S⁷, Sun WH⁴, Chen CC⁸.

involvement of trpv1 and tdag8 in pruriception associated with noxious acidosis

Itch and pain are closely related but distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether proton can evoke itch like other algogens at the basis of spatial contrast activation of single nociceptors. Here, we report that (1) citric acid (0.2 M) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin; (2) acidified buffer elevated intracellular calcium levels in dorsal root ganglion (DRG) pruriceptors; (3) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1 but neither ASIC3 nor TRPA1 are involved in the acidic citrate-induced scratching response. Furthermore, one of the proton-sensing G-protein-coupled receptors, TDAG8, was highly (∼71%) expressed in Nppb⁺ DRG pruriceptors. Acidic citrate but not α-methyl-5-HT, chloroquine, compound 48/80 or bile acid-induced itch was markedly decreased in TDAG8^-/- mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, proton could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.

The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.

Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.