Abstract:

To investigate the role and mechanism of sirtuin 1 （SIRT1）??-mediated deacetylation of high mobility group box 1 （HMGB1） in chronic rhinosinusitis with nasal polyps （CRSwNP）. CRSwNP cellular model was established using lipopolysaccharide （LPS）?-induced human primary nasal epithelial cells （HNEpC）. The effects of LPS on cell viability， expression of CRSwNP-related proteins （NLRP3， Caspase-1， TSLP）， SIRT1 expression， acetylation level and translocation of HMGB1， mRNA levels of inflammatory cytokines， and pyroptosis were examined. Furthermore， SIRT1 overexpression model was constructed or cells were treated with exogenous lactate to investigate the roles of SIRT1 and lactate in LPS-mediated pyroptosis. Compared with the control group， 30 μg·mL^-1 LPS had no effect on the viability of HNEpC cells but significantly increased the protein expression of NLRP3， Caspase-1， and TSLP， as well as the mRNA levels of inflammatory cytokines. Simultaneously， LPS significantly downregulated SIRT1 expression， increased HMGB1 acetylation and translocation， induced pyroptosis， and lactate production. Compared with the LPS-treated group， the SIRT1 overexpression group exhibited decreased HMGB1 acetylation and translocation， reduced release of inflammatory cytokines， inhibited pyroptosis， and significantly decreased lactate content in the supernatant. Exogenous lactate significantly downregulated SIRT1 protein expression， promoted HMGB1 acetylation and translocation， and enhanced the release of inflammatory cytokines and lactate. In summary， SIRT1 attenuates LPS-induced acetylation and translocation of HMGB1 in HNEpC， thereby ameliorating pyroptosis and reducing cellular inflammation.

Key words: chronic rhinosinusitis with nasal polyps, sirtuin 1, acetylation, high mobility group box 1, pyroptosis, inflammation

摘要：

研究旨在探讨沉默信号调节因子1（ sirtuin 1，SIRT1）介导的高迁移率族蛋白B1（high mobility group box 1，HMGB1）去乙酰化在慢性鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）中的作用及机制。采用脂多糖（lipopolysaccharide，LPS）诱导人原代鼻粘膜上皮细胞（ human primary nasal epithelial cells，HNEpC）构建CRSwNP细胞模型，检测LPS对细胞活力、CRSwNP相关蛋白表达（NLRP3、Caspase-1、TSLP）、SIRT1表达、HMGB1乙酰化水平及转位、炎症因子mRNA水平以及细胞焦亡的影响。进一步构建SIRT1过表达模型，给予细胞外源乳酸处理，检测SIRT1及乳酸在LPS介导的细胞焦亡中的作用。结果发现，与对照组相比，30 μg·mL^-1 LPS对HNEpC细胞活力无损伤，且显著增加NLRP3、Caspase-1、TSLP蛋白表达以及炎症因子mRNA水平；同时显著下调SIRT1表达，提高HMGB1乙酰化水平及转位，诱导细胞焦亡及乳酸产生。与LPS处理组相比，SIRT1过表达组细胞HMGB1乙酰化及转位下降，炎症因子释放减少，细胞焦亡被抑制，上清乳酸含量显著减少；外源性乳酸显著下调细胞SIRT1蛋白表达，促进HMGB1乙酰化及转位，促进炎症因子及乳酸释放。综上，SIRT1能够减轻LPS诱导的HNEpC中HMGB1的乙酰化和转位，进而改善细胞焦亡，减少细胞炎症。

关键词: 慢性鼻窦炎伴鼻息肉, 沉默信号调节因子1, 乙酰化, 高迁移率族蛋白B1, 细胞焦亡, 炎症