PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models

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Abstract

PAR2 has been proposed to contribute to lesion formation and intense itch in atopic dermatitis. Here, we tested the ability of a cell-penetrating pepducin, PZ-235, to mitigate the potentially deleterious effects of PAR2 in models of atopic dermatitis. PZ-235 significantly inhibited PAR2-mediated expression of inflammatory factors NF-κB, TSLP, TNF-α and differentiation marker K10 by 94%–98% (P < 0.001) in human keratinocytes and suppressed IL-4 and IL-13 by 68%–83% (P < 0.05) in mast cells. In delayed pepducin treatment models of oxazolone- and DNFB-induced dermatitis, PZ-235 significantly attenuated skin thickening by 43%–100% (P < 0.01) and leukocyte crusting by 57% (P < 0.05), and it inhibited ex vivo chemotaxis of leukocytes toward PAR2 agonists. Daily PZ-235 treatment of filaggrin-deficient mice exposed to dust mite allergens for 8 weeks significantly suppressed total leukocyte and T-cell infiltration by 50%–68%; epidermal thickness by 60%–77%; and skin thickening, scaling, excoriation, and total lesion severity score by 46%–56%. PZ-235 significantly reduced itching caused by wasp venom peptide degranulation of mast cells in mice by 51% (P < 0.05), which was comparable to the protective effects conferred by PAR2 deficiency. Taken together, these results suggest that a PAR2 pepducin may confer broad therapeutic benefits as a disease-modifying treatment for atopic dermatitis and itch.

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Barr, T. P., Garzia, C., Guha, S., Fletcher, E. K., Nguyen, N., Wieschhaus, A. J., … Kuliopulos, A. (2019). PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models. Journal of Investigative Dermatology, 139(2), 412–421. https://doi.org/10.1016/j.jid.2018.08.019

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