Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China; Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China.
Int Immunopharmacol. 2023 Nov;124(Pt B):110958. doi: 10.1016/j.intimp.2023.110958. Epub 2023 Sep 21.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, erythema, and skin barrier dysfunction. Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. However, the role of GSDMD in the pathogenesis of AD remains unclear. Through the analysis of publicly available Gene Expression Omnibus (GEO) datasets, we observed an upregulation of Gsdmd mRNA in the skin tissue of AD patients. Moreover, we delved into the impact of GSDMD deletion and inhibition on AD-like skin lesions using a mouse model induced by the topical application of oxazolone (Oxa). We found that mice lacking GSDMD exhibited relieved AD signs and symptoms in terms of reduced skin thickness, scarring and scratching behavior compared to wild-type mice after induction of AD-like skin lesions. This was associated with decreased infiltration of inflammatory cells, reduced epidermal thickness, and decreased serum levels of IgE and IL-4. Western blot analysis further revealed decreased GSDMD cleavage in the skin of GSDMD knockout mice, and reduced expression of IL-1β and IL-18. Inhibition of GSDMD using the pharmacological agent disulfiram or the herbal compound matrine significantly attenuated the symptoms of AD-like skin lesions in wild-type mice, GSDMD cleavage and pro-inflammatory cytokines were reduced as well. Our results suggest that GSDMD-mediated pyroptosis plays a critical role in the development of AD-like skin lesions, and targeting GSDMD may be a promising therapeutic strategy for AD.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其特征为瘙痒、红斑和皮肤屏障功能障碍。Gasdermin D（GSDMD）是一种称为细胞焦亡的炎症细胞死亡机制的关键执行者。然而，GSDMD 在 AD 发病机制中的作用尚不清楚。通过对公开的基因表达综合数据库（GEO）数据集进行分析，我们观察到 AD 患者皮肤组织中 Gsdmd mRNA 的上调。此外，我们通过使用氧嗪酸钾（Oxa）局部应用诱导的小鼠模型，研究了 GSDMD 缺失和抑制对 AD 样皮肤损伤的影响。我们发现与野生型小鼠相比，缺乏 GSDMD 的小鼠在诱导 AD 样皮肤损伤后，皮肤厚度、疤痕和搔抓行为等 AD 体征和症状明显减轻。这与炎症细胞浸润减少、表皮厚度降低以及血清 IgE 和 IL-4 水平降低有关。Western blot 分析进一步显示 GSDMD 敲除小鼠皮肤中 GSDMD 裂解减少，IL-1β 和 IL-18 的表达减少。使用药理学试剂双硫仑或草药化合物苦参碱抑制 GSDMD 可显著减轻野生型小鼠的 AD 样皮肤损伤症状，减少 GSDMD 裂解和促炎细胞因子的表达。我们的研究结果表明，GSDMD 介导的细胞焦亡在 AD 样皮肤损伤的发生发展中起关键作用，靶向 GSDMD 可能是 AD 的一种有前途的治疗策略。
