TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis

Abstract

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 inflammation and scratching behavior. These findings support a central role for TRPA1 and SP in the integration of immune and neuronal mechanisms leading to chronic inflammatory responses and pruritus associated with contact dermatitis.—Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A., Jordt, S. E., TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 27, 3549–3563 (2013). http://www.fasebj.org

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

“…To examine whether these pathways also contribute to itch in poison ivy ACD, we established a mouse model induced by cutaneous sensitization and challenge with urushiol. This model mimics many key clinical features of poison ivy-induced ACD, including skin inflammation and severe itch (16). TRPA1 inhibition was less efficacious in this model, suggesting that poison ivy ACD engages as-yet-unknown inflammatory and pruritic pathways (16).…”

“…Behavioral experiments were performed as described (16). All behavioral tests were performed by an experimenter blinded to experimental conditions.…”

“…suppress itch in a mouse ACD model induced by the synthetic allergen oxazolone (16). To examine whether these pathways also contribute to itch in poison ivy ACD, we established a mouse model induced by cutaneous sensitization and challenge with urushiol.…”

“…These include cytokines such as IL-31, CXCL-10, or TSLP (thymic stromal lymphopoietin); transmitters such as serotonin; and their cognate receptors and coupled ion channels (13-15). These studies used either chemicals eliciting acute itch (such as chloroquine) or ACD rodent models induced by synthetic allergens not present in the environment [2,4-dinitrofluorobenzene (DNFB) oxazolone, and others] (14,(16)(17)(18).…”

Propacetamol-Induced Injection Pain Is Associated with Activation of Transient Receptor Potential Vanilloid 1 Channels

“…Furthermore, the deletion of TRPA1 in mice revealed a crucial role for TRPA1 in hapten-induced contact hypersensitivity. In this model, TRPA1 in the skin controls levels of inflammatory cytokines (interleukin-4, interleukin-6) and nerve growth factor as well as substance P and serotonin, which induces pruritogenic responses (Liu et al, 2013). Berl et al (1998) proposed a mechanism of how PPCM induces occupational contact dermatitis in sensitized nurses who had positive patch tests to PPCM but negative patch tests to PCM.…”