PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models
Barr, T.P. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Garzia, C. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Guha, S. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Fletcher, E.K. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Nguyen, N. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Wieschhaus, A.J. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Ferrer i Caubet, Lluís (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Covic, L. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)
Kuliopulos, A. (Tufts University School of Medicine. Center of Hemostasis and Thrombosis Research)

Data:	2019
Resum:	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.
Nota:	We thank Joe Stevens for assistance in conducting dermatitis models. This study was funded in whole or in part by AR067617 (AK, LC) from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Animals ; Cell-Penetrating Peptides ; Dermatitis, Atopic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Keratinocytes ; Male ; Mice ; Pruritus ; Receptor, PAR-2
Publicat a:	The Journal of investigative dermatology, Vol. 139 Núm. 2 (february 2019) , p. 412-421, ISSN 1523-1747

DOI: 10.1016/j.jid.2018.08.019
PMID: 30287285

21 p, 1.2 MB

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