Allergic contact dermatitis is a common skin disease associated with inflammation and persistent pruritus. Transient receptor potential (TRP) ion channels in skin-innervating sensory neurons mediate acute inflammatory and pruritic responses following exogenous stimulation and may contribute to allergic responses. Genetic ablation or pharmacological inhibition of TRPA1, but not TRPV1, inhibited skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine-resistant scratching behavior in mice exposed to the haptens, oxazolone and urushiol, the contact allergen of poison ivy. Hapten-challenged skin of TRPA1-deficient mice contained diminished levels of inflammatory cytokines, nerve growth factor, and endogenous pruritogens, such as substance P (SP) and serotonin. TRPA1-deficient sensory neurons were defective in SP signaling, and SP-induced scratching behavior was abolished in Trpa1−/− mice. SP receptor antagonists, such as aprepitant inhibited both hapten-induced cutaneous i...

TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.

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Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans

Background: Mechanical forces modulate wound healing and scar formation through mechanotransduction. In response to mechanical stimulation, neuropeptides are released from peripheral terminals of primary afferent sensory neurons, influencing skin and immune cell functions and increasing vascular permeability, causing neurogenic inflammation. Methods: A computer-controlled device was used to stretch murine skin. C57Bl6 mice (n = 26) were assigned to a cyclical square-wave tensile stimulation for 4 hours or continuous stimulation for 4 hours. Stretched skin was analyzed for expression of the neuropeptides, substance P and calcitonin gene-related peptide, their receptors (NK1R and calcitonin gene-related peptide receptor component protein), and growth factors (nerve growth factor, transforming growth factor β1, vascular endothelial growth factor, and epidermal growth factor) using immunohistochemistry and real-time reverse-transcriptase polymerase chain reaction. Results: Cyclical stimulation resulted in a significant increase in expression of neuropeptides and growth factors, whereas the corresponding peptide receptors were down-regulated. Transcription of neuropeptide mRNA was elevated in stretched skin, which proves that neuropeptides are released from not only peripheral terminals of nerve fibers but also resident skin cells. Conclusions: The authors' results suggest that skin stretching may alter cell physiology by stimulating neuropeptide expression, and that cyclical mechanical force may be more effectively stimulating mechanosensitive nociceptors or mechanoreceptors (mechanosensors) on cells.

Analysis of neuropeptides in stretched skin.

Purpose of reviewRecent studies have advanced our understanding that allergic inflammation triggers neuronal dysfunction, thereby modulating inflammation-related changes in affected tissues including the skin. Vice versa, evidence has emerged that inflammatory responses are controlled by neurons. Mo

Neuroimmune interactions in allergic skin diseases.

Nerve fibers and sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) have been reported to be involved in allergic contact dermatitis (ACD). In the present study, we investigated the general innervation (using antibody against protein gene product 9.5, PGP 9.5), axonal growth (using antibody against growth associated protein, GAP-43), CGRP, and substance P with its receptor neurokinin 1 (NK1), in positive epicutaneous reactions to nickel sulphate from nickel-allergic patients, at the peak of inflammation, 72 hr after challenge with the antigen. There was an increased (p < 0.01) number of GAP-43 positive fibers in the eczematous compared with control skin, indicating an increased axonal growth already at 72 hr postchallenge. Double staining revealed a coexpression of CGRP and GAP-43 on dermal nerve fibers. There was no difference in the number of substance P and CGRP positive nerve fibers between eczematous and control skin. However, semiquantification analyses showed an increased ...

R. Al-Tawil

Papers

Upregulation of the axonal growth and the expression of substance P and its NK1 receptor in human allergic contact dermatitis.