Abstract
Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.
Highlights
Both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways
Since pre-sensitization is critical to the induction of T cell-mediated immunity in ACD, we investigated the effect of pre-sensitization on Squaric acid dibutylester (SADBE)-induced inflammation and spontaneous scratching
These results suggest that SADBE can evoke both lymphocyte-dependent and lymphocyte-independent inflammatory responses, similar to those seen in ACD and irritant contact dermatitis (ICD), which is a nonallergic inflammatory reaction[20]
Summary
Both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Recent studies have shown that enhanced excitability of primary sensory neurons expressing itch-mediating mas-related G protein-coupled receptors MRGPRA3 and MRGPRD and several chemokines and chemokine receptors were correlated with sensory hypersensitivity in response to pre-sensitization and subsequent challenges with SADBE in mice[6, 15], thereby providing a cellular mechanism accounting for spontaneous scratching in this mouse model of ACD. We show that SADBE is an activator of both TRPA1 and TRPV1 by directly interacting with specific amino acid residues located at their intracellular protein domains Both sensory TRP channels are required for generating the SADBE-induced persistent itch. Our results suggest that chronic skin inflammation and persistent itch in the SADBE-induced CHS are mediated by distinct molecular mechanisms that rely on the functions of sensory TRP channels
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