2016.11.25

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

2016.11.18

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

Abstract

Itch and pain are unpleasant sensations that distress many patients with disease. However, most studies have focused on the neural mechanisms of pain, and much less effort has been devoted to itch. It has been reported that itch and pain might share a common pathway, and γ-aminobutyric acid type A (GABA(A)) receptors in the central nucleus of the amygdala (CeA) are involved in pain modulation. However, the contribution of GABAA receptors in the CeA to the modulation of itch remains poorly understood. Herein, we report that bilateral intra-CeA microinjection of a selective GABAA receptor agonist muscimol hydrochloride (Mus; 50 ng per side), but not a selective GABAA receptor antagonist bicuculline (Bic; 20 ng per side) or vehicle, showed significant analgesic effects, reflected by an increase in tail-flick latency and a decrease in allyl isothiocyanate (mustard oil)-evoked ipsilateral forelimb wipes. More importantly, rats subjected to intra-CeA infusion of Bic showed a significantly greater number of scratching bouts and time in acute and chronic pruritus animal models than control rats. Conversely, intra-CeA infusion of Mus in animal models dramatically decreased the number of scratching bouts and time compared with control rats. In addition, intra-CeA infusion of Bic or Mus at the current dose had no obvious effects on other behaviors including locomotor activity and spontaneous facial grooming in rats subjected to cheek microinjection of 5-hydroxytryptamine. Taken together, these results indicate that the GABA(A) receptor-mediated inhibitory system in the CeA is involved in itch modulation as well as is known in pain control.

PERSPECTIVE:

Itch, especially chronic itch, remains a challenge in clinic. Results of this study showed that the GABAA receptors in the CeA play an important role in itch modulation, which might help us to better understand the mechanisms of itch and subsequently develop novel mechanisms-based strategies to treat chronic itch in clinic.

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

Journal Club 2016.11.04.

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

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