Increased Cis-to-Trans Urocanic Acid Ratio in the Skin of Chronic Urticaria Leads to the Enhancement of Mast Cell Degranulation

Rationale: Increased filaggrin expression was positively correlated with urticaria severity in our previous study. However, the role of filaggrin breakdown products (FBP) in the pathogenesis of CU has not been studied.

Methods: FBP, including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA) were quantitated in stratum corneum (SC) samples collected from volar forearm regions (6 consecutive tapes) employing UPLC-MS/MS from 10 CSU, 10 atopic dermatitis (AD) and 10 normal subjects. In vitro effects of cis- and trans-UCA on human mast cell degranulation were assessed by beta-hexosaminidase release assay using LAD2 cells.

Results: With normalization by protein content, total amount of FBP and PCA content was significantly decreased in lesional (21.56±20.2 and 16.70±15.4 ng/mg protein, respectively, P<0.01) AD skins as compared to NC (63.86±21.6 and 49.14±16.3). However, those were not significantly different in CSU lesions (44.54±31.2 and 34.48±23.6) compared with NC. Trans-UCA, the primary isomer of the UCA in NC, was significantly decreased in CSU and AD. The proportion of cis-UCA was significantly higher in CSU skin (0.44±0.24, P<0.01) compared with AD (0.14±0.20) and NC (0.10±0.12). Both TEWL and pH were significantly increased in AD lesions compared with CSU lesions. Cis-UCA dose-dependently enhanced the IgE- and calcium-mediated degranulation of LAD2 cells (P<0.001), which was not observed with trans-UCA.

Conclusions: FBP deficiency in AD was confirmed in the association with a significant increase in TEWL and pH in AD. Increased ratio of cis-to-trans-UCA, and decreased epidermal pH in CU can be associated with CU pathogenesis. Cis-UCA could contribute to the pathogenesis of CU by enhancing mast cell degranulation.