Center of Hemostasis and Thrombosis Research, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA.
Department of Dermatology, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, USA.
J Invest Dermatol. 2019 Feb;139(2):412-421. doi: 10.1016/j.jid.2018.08.019. Epub 2018 Oct 1.
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.
PAR2 被认为有助于特应性皮炎的病变形成和剧烈瘙痒。在这里，我们测试了一种穿透细胞的肽，PZ-235，在特应性皮炎模型中减轻 PAR2 潜在有害影响的能力。PZ-235 显著抑制了 PAR2 介导的人角质形成细胞中炎症因子 NF-κB、TSLP、TNF-α 和分化标记物 K10 的表达，抑制率为 94%-98%（P < 0.001），并抑制肥大细胞中 IL-4 和 IL-13 的表达，抑制率为 68%-83%（P < 0.05）。在迟发型肽治疗模型中，PZ-235 显著减轻了 oxazolone 和 DNFB 诱导的皮炎的皮肤增厚，抑制率为 43%-100%（P < 0.01），并抑制了白细胞结壳，抑制率为 57%（P < 0.05），并抑制了白细胞对 PAR2 激动剂的体外趋化性。对暴露于尘螨过敏原 8 周的 filaggrin 缺陷小鼠进行每日 PZ-235 治疗，显著抑制了总白细胞和 T 细胞浸润，抑制率为 50%-68%；表皮厚度，抑制率为 60%-77%；皮肤增厚、鳞屑、抓挠和总病变严重程度评分，抑制率为 46%-56%。PZ-235 显著减少了小鼠肥大细胞蜂毒肽脱颗粒引起的瘙痒，抑制率为 51%（P < 0.05），与 PAR2 缺陷赋予的保护作用相当。综上所述，这些结果表明，PAR2 肽可能作为一种疾病修饰治疗方法，为特应性皮炎和瘙痒提供广泛的治疗益处。
