烟酰胺单核苷酸通过抑制SIRT3 SUMO化减轻哮喘气道上皮屏障功能障碍
2023/12/20
摘要
背景：烟酰胺腺嘌呤二核苷酸(NAD)是调节基本生物过程的细胞代谢必需元素。越来越多的证据表明，NAD的下降是各种疾病和衰老的共同病理因素。然而，其在哮喘气道上皮屏障功能中的作用尚不清楚。
方法：本研究旨在探讨通过补充 NAD 前体物烟酰胺单核苷酸（NMN）来恢复细胞 NAD 浓度对治疗过敏性哮喘的疗效，并研究 SIRT3 在介导 NAD 前体物作用中的作用。
结果：在这项研究中，NMN减轻了屋尘螨(HDM)诱导的哮喘小鼠的气道炎症和减少黏液分泌。在体外和体内实验中，它也减轻了HDM诱导的哮喘的气道上皮屏障破坏。但抑制SIRT3表达后，NMN的作用消失。机制上，HDM诱导SIRT3 SUMO化和蛋白酶体降解。这两个SIRT3 SUMO修饰位点的突变增强了SIRT3的稳定性。此外，SIRT3被SENP1靶向，作用于脱耦联SUMO。NMN可逆转HDM诱导的SENP1表达下调。
结论：总之，这些研究结果表明，NMN 可通过抑制哮喘中的 SIRT3 SUMO化减轻气道上皮屏障功能障碍。阻断 SIRT3 SUMO化可用于治疗过敏性哮喘。
Nicotinamide mononucleotide attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma
Jiayuan Liang , Chi Zhou , Changyun Zhang et al.
Abstract
BACKGROUND:Nicotinamide adenine dinucleotide (NAD) is an essential element in cellular metabolism that regulates fundamental biological processes. Growing evidence suggests that a decline in NAD is a common pathological factor in various diseases and aging. However, its role in airway epithelial barrier function in response to asthma remains underexplored.
METHODS:The current study aims to explore the efficacy of restoring cellular NAD concentration through supplementation with the NAD precursor, nicotinamide mononucleotide (NMN), in the treatment of allergic asthma and to investigate the role of SIRT3 in mediating the effects of NAD precursors.
RESULTS: In this research, NMN alleviated airway inflammation and reduced mucus secretion in house dust mite (HDM)-induced asthmatic mice. It also mitigated airway epithelial barrier disruption in HDM-induced asthma in vitro and in vivo. But inhibition of SIRT3 expression abolished the effects of NMN. Mechanistically, HDM induced SIRT3 SUMOylation and proteasomal degradation. Mutation of these two SIRT3 SUMO modification sites enhanced the stability of SIRT3. Additionally, SIRT3 was targeted by SENP1 which acted to deconjugate SUMO. And down-regulation of SENP1 expression in HDM-induced models was reversed by NMN.
CONCLUSIONS: Collectively, these findings suggest that NMN attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma. Blockage of SIRT3 SUMOylation emerges as for the treatment of allergic asthma.
背景：烟酰胺腺嘌呤二核苷酸(NAD)是调节基本生物过程的细胞代谢必需元素。越来越多的证据表明，NAD的下降是各种疾病和衰老的共同病理因素。然而，其在哮喘气道上皮屏障功能中的作用尚不清楚。
方法：本研究旨在探讨通过补充 NAD 前体物烟酰胺单核苷酸（NMN）来恢复细胞 NAD 浓度对治疗过敏性哮喘的疗效，并研究 SIRT3 在介导 NAD 前体物作用中的作用。
结果：在这项研究中，NMN减轻了屋尘螨(HDM)诱导的哮喘小鼠的气道炎症和减少黏液分泌。在体外和体内实验中，它也减轻了HDM诱导的哮喘的气道上皮屏障破坏。但抑制SIRT3表达后，NMN的作用消失。机制上，HDM诱导SIRT3 SUMO化和蛋白酶体降解。这两个SIRT3 SUMO修饰位点的突变增强了SIRT3的稳定性。此外，SIRT3被SENP1靶向，作用于脱耦联SUMO。NMN可逆转HDM诱导的SENP1表达下调。
结论：总之，这些研究结果表明，NMN 可通过抑制哮喘中的 SIRT3 SUMO化减轻气道上皮屏障功能障碍。阻断 SIRT3 SUMO化可用于治疗过敏性哮喘。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Int Immunopharmacol. 2023 Dec 7:127:111328 DOI: 10.1016/j.intimp.2023.111328）
（Int Immunopharmacol. 2023 Dec 7:127:111328 DOI: 10.1016/j.intimp.2023.111328）
Nicotinamide mononucleotide attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma
Jiayuan Liang , Chi Zhou , Changyun Zhang et al.
Abstract
BACKGROUND:Nicotinamide adenine dinucleotide (NAD) is an essential element in cellular metabolism that regulates fundamental biological processes. Growing evidence suggests that a decline in NAD is a common pathological factor in various diseases and aging. However, its role in airway epithelial barrier function in response to asthma remains underexplored.
METHODS:The current study aims to explore the efficacy of restoring cellular NAD concentration through supplementation with the NAD precursor, nicotinamide mononucleotide (NMN), in the treatment of allergic asthma and to investigate the role of SIRT3 in mediating the effects of NAD precursors.
RESULTS: In this research, NMN alleviated airway inflammation and reduced mucus secretion in house dust mite (HDM)-induced asthmatic mice. It also mitigated airway epithelial barrier disruption in HDM-induced asthma in vitro and in vivo. But inhibition of SIRT3 expression abolished the effects of NMN. Mechanistically, HDM induced SIRT3 SUMOylation and proteasomal degradation. Mutation of these two SIRT3 SUMO modification sites enhanced the stability of SIRT3. Additionally, SIRT3 was targeted by SENP1 which acted to deconjugate SUMO. And down-regulation of SENP1 expression in HDM-induced models was reversed by NMN.
CONCLUSIONS: Collectively, these findings suggest that NMN attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma. Blockage of SIRT3 SUMOylation emerges as for the treatment of allergic asthma.
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