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

T.P. Barr, C. Garzia, S. Guha, E.K. Fletcher, N. Nguyen, A.J. Wieschhaus, Lluís Ferrer i Caubet, L. Covic, A. Kuliopulos

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53 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)0412-421
Number of pages10
JournalThe Journal of investigative dermatology
Volume139
Issue number2
DOIs
Publication statusPublished - 2019

Keywords

  • Animals
  • Cell-Penetrating Peptides
  • Dermatitis, Atopic
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Keratinocytes
  • Male
  • Mice
  • Pruritus
  • Receptor, PAR-2

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