Jeon Hyejin, Seo Yohan, Lee Wook-Joo, Heo Yunkyung, Shim Won-Sik, Namkung Wan
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
Department of Bio-Nanomaterials, Bio Campus of Korea Polytechnics, 112 Dongan-ro, Ganggeong-up, Nonsan 32943, Republic of Korea.
Int J Mol Sci. 2025 Sep 13;26(18):8920. doi: 10.3390/ijms26188920.
Atopic dermatitis is a chronic inflammatory skin disorder characterized by persistent inflammation and severe pruritus. Current anti-inflammatory agents carry risks of long-term adverse effects, while antihistamines provide limited relief of pruritus. Protease-activated receptor 2 (PAR2) has emerged as a critical mediator of both inflammation and pruritus, representing a promising therapeutic target. In this study, we investigated the therapeutic potential of punicalagin (PCG), a potent PAR2 antagonist, in atopic dermatitis. PCG fully and potently inhibited trypsin-induced PAR2 activation in HaCaT cells with an IC of 1.30 µM, exhibiting over 40-fold greater selectivity over PAR1. PCG significantly inhibited PAR2-induced phosphorylation of ERK1/2 and NF-κB in both HaCaT and human dermal fibroblast cells and reduced IL-8 secretion in HaCaT cells. In addition, PCG did not significantly affect other pruritus-related GPCRs including H1R, H4R, TGR5, 5HT2A, 5HT2B, and MRGPRX2 at 30 µM. Notably, PCG strongly blocked PAR2-AP-induced scratching in mice. In addition, PCG improved skin lesions, reduced dermatitis severity scores, and alleviated scratching behavior in a DNFB-induced atopic dermatitis model. These effects were associated with reduced epidermal thickness, decreased serum TSLP levels, and inhibition of PAR2-dependent calcium signaling in dorsal root ganglion neurons. These findings demonstrate that PCG is a selective PAR2 antagonist that effectively alleviates both inflammatory and pruritic symptoms of atopic dermatitis, suggesting its potential as a novel therapeutic agent.
特应性皮炎是一种慢性炎症性皮肤病，其特征为持续性炎症和严重瘙痒。目前的抗炎药物存在长期不良反应的风险，而抗组胺药对瘙痒的缓解作用有限。蛋白酶激活受体2（PAR2）已成为炎症和瘙痒的关键介质，是一个有前景的治疗靶点。在本研究中，我们调查了石榴皮素（PCG），一种有效的PAR2拮抗剂，在特应性皮炎中的治疗潜力。PCG在HaCaT细胞中能完全且强效地抑制胰蛋白酶诱导的PAR2激活，IC50为1.30µM，对PAR1的选择性超过40倍。PCG在HaCaT细胞和人皮肤成纤维细胞中均显著抑制PAR2诱导的ERK1/2和NF-κB磷酸化，并减少HaCaT细胞中IL-8的分泌。此外，在30µM时，PCG对包括H1R、H4R、TGR5、5HT2A、5HT2B和MRGPRX2在内的其他瘙痒相关GPCR没有显著影响。值得注意的是，PCG强烈阻断PAR2-AP诱导的小鼠抓挠行为。此外，在二硝基氟苯诱导的特应性皮炎模型中，PCG改善了皮肤损伤，降低了皮炎严重程度评分，并减轻了抓挠行为。这些作用与表皮厚度降低、血清TSLP水平降低以及背根神经节神经元中PAR2依赖性钙信号传导的抑制有关。这些发现表明，PCG是一种选择性PAR2拮抗剂，可有效缓解特应性皮炎的炎症和瘙痒症状，提示其作为一种新型治疗药物的潜力。
