Lai Shuqin, Chen Huaqing, Ji Xiaojuan, Zhu Wenjie, Wu Zhiwei, Huang Shan, Lin Chunli, Yang Tao, Zeng Zhaolin, Li Longnian
Department of Dermatology, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.
Department of Laser and cosmetic Dermatology, Ganzhou Dermatosis Hospital, Ganzhou 341000, China.
Int Immunopharmacol. 2025 Feb 6;147:114036. doi: 10.1016/j.intimp.2025.114036. Epub 2025 Jan 7.
Psoriasis is a chronic inflammatory skin disease regulated by autoimmunity, and pyroptosis plays an important role in this condition. This research sought to examine the function and potential molecular pathway of Gasdermin D (GSDMD) in psoriasis.
GSDMD expression was examined by immunohistochemistry in biopsied skin tissues from patients with psoriasis. Pyroptosis-related genes and inflammatory factors were quantified using qRT-PCR and ELISA, respectively. HaCaT cells were treated with M5 cytokines to develop an in vitro psoriasis model, while imiquimod (IMQ) was administered to construct an in vivo psoriasis model. To counteract the inhibition of the NOD-like receptor (NLR) pathway caused by GSDMD knockdown, the pathway activator M-TriDAP was employed.
In the lesional skin tissues of patients with psoriasis, GSDMD expression was highly expressed. The levels of pro-pyroptosis mediators were increased, whereas the level of anti-inflammatory factor was lowered. GSDMD knockdown and disulfiram treatment inhibited pyroptosis and promoted apoptosis in M5-induced HaCaT cells. In the IMQ-induced psoriasis-like mouse model, GSDMD knockdown suppressed pyroptosis and improved skin lesion severity, alleviating erythema, epidermal thickness, and inflammatory cell infiltration. Mechanistically, GSDMD knockdown inhibited the NLR pathway, accompanied by reduced protein levels of NLRP3, NOD1, NOD2, and PYCARD. NLR pathway activator, M-TriDAP treatment significantly reversed the effects of GSDMD knockdown on psoriasis progression.
Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NLR signaling pathway, presenting a novel potential strategy for psoriasis treatment.
银屑病是一种由自身免疫调节的慢性炎症性皮肤病，细胞焦亡在该疾病中起重要作用。本研究旨在探讨Gasdermin D（GSDMD）在银屑病中的功能及潜在分子途径。
采用免疫组织化学法检测银屑病患者活检皮肤组织中GSDMD的表达。分别使用qRT-PCR和ELISA定量细胞焦亡相关基因和炎症因子。用M5细胞因子处理HaCaT细胞以建立体外银屑病模型，同时给予咪喹莫特（IMQ）构建体内银屑病模型。为抵消GSDMD敲低对NOD样受体（NLR）途径的抑制作用，采用该途径激活剂M-TriDAP。
在银屑病患者的皮损组织中，GSDMD表达高。促细胞焦亡介质水平升高，而抗炎因子水平降低。GSDMD敲低和双硫仑处理抑制M5诱导的HaCaT细胞中的细胞焦亡并促进凋亡。在IMQ诱导的银屑病样小鼠模型中，GSDMD敲低抑制细胞焦亡并改善皮肤病变严重程度，减轻红斑、表皮厚度和炎性细胞浸润。机制上，GSDMD敲低抑制NLR途径，同时NLRP3、NOD1、NOD2和PYCARD的蛋白水平降低。NLR途径激活剂M-TriDAP处理显著逆转GSDMD敲低对银屑病进展的影响。
敲低GSDMD通过阻断NLR信号通路抑制银屑病中的细胞焦亡，为银屑病治疗提供了一种新的潜在策略。
