Huang Wei, Chen Xi, Liu Zizhen, Li Changwu, Wei Xin, Zhan Jiabin, Qiu Quan, Zheng Jing
Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan Province, PR China.
World Allergy Organ J. 2024 Sep 5;17(9):100963. doi: 10.1016/j.waojou.2024.100963. eCollection 2024 Sep.
Allergic rhinitis (AR) is a global health issue affecting millions of individuals worldwide. Pyroptosis has emerged as a major player in the development of AR, and targeting its inhibition with specific drugs holds promise for AR treatment. However, a comprehensive understanding of the precise mechanisms underlying pyroptosis in AR remains to be explored, warranting further investigation.
This study aims to elucidate the roles of HMGB1, Sphk1, and HDAC4 in regulating human nasal epithelial cell (hNEC) pyroptosis and AR.
An AR cell culture model and AR mouse model were established. Western blot, ELISA, histological staining, and flow cytometry were utilized to confirm the gene and protein expression. The interactions among Sphk1, HDAC4, and HMGB1 were validated through ChIP, Co-IP, and Dual-luciferase assay.
We identified that the expression levels of Sphk1, HMGB1, and inflammasome components, including IL-18, and IL-1β were elevated in AR patients and mouse models. Knockdown of Sphk1 inhibited hNEC pyroptosis induced by dust mite allergen. Overexpression of HDAC4 suppressed HMGB1-mediated pyroptosis in hNECs. In addition, HDAC4 was found to mediate the transcriptional regulation of HMGB1 via MEF2C, a transcription factor. Additionally, Sphk1 was shown to interact with CaMKII-δ, promoting the phosphorylation of HDAC4 and inhibiting its cytoplasmic translocation. Knockdown of HDAC4 reversed the effect of Sphk1 knockdown on pyroptosis. These discoveries offer a glimpse into the molecular mechanisms underlying AR and suggest potential therapeutic targets for the treatment of this condition.
过敏性鼻炎（AR）是一个全球性的健康问题，影响着全球数百万人。细胞焦亡已成为AR发病机制中的一个主要因素，用特定药物靶向抑制细胞焦亡有望用于AR的治疗。然而，对AR中细胞焦亡的确切机制仍有待全面了解，需要进一步研究。
本研究旨在阐明高迁移率族蛋白B1（HMGB1）、鞘氨醇激酶1（Sphk1）和组蛋白去乙酰化酶4（HDAC4）在调节人鼻上皮细胞（hNEC）焦亡和AR中的作用。
建立AR细胞培养模型和AR小鼠模型。采用蛋白质免疫印迹法、酶联免疫吸附测定法、组织学染色和流式细胞术来确认基因和蛋白质表达。通过染色质免疫沉淀法（ChIP）、免疫共沉淀法（Co-IP）和双荧光素酶测定法验证Sphk1、HDAC4和HMGB1之间的相互作用。
我们发现，AR患者和小鼠模型中Sphk1、HMGB1以及包括白细胞介素18（IL-18）和白细胞介素1β（IL-1β）在内的炎性小体成分的表达水平升高。敲低Sphk1可抑制尘螨变应原诱导的hNEC焦亡。过表达HDAC4可抑制HMGB1介导的hNEC焦亡。此外，发现HDAC4通过转录因子心肌增强因子2C（MEF2C）介导HMGB1的转录调控。此外，Sphk1被证明与钙/钙调蛋白依赖性蛋白激酶II-δ（CaMKII-δ）相互作用，促进HDAC4的磷酸化并抑制其向细胞质的转运。敲低HDAC4可逆转敲低Sphk1对焦亡的影响。这些发现揭示了AR潜在的分子机制，并为这种疾病的治疗提供了潜在的治疗靶点。
