Liu Lu, Huan Liting, Zhang Yu, Wei Wei, Chen Zhihai, Xu Di, Huang Xiufeng, Tan Yaoxi, Li Hongxing
Department of Respiratory and Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China;
Department of Internal Medicine, Zibo Municipal Hospital for Infectious Diseases, Zibo, China.
Allergol Immunopathol (Madr). 2022 Mar 1;50(2):96-103. doi: 10.15586/aei.v50i2.568. eCollection 2022.
Asthma, characterized by dysfunction of airway epithelial cells, is regarded as a chronic inflammatory disorder in the airway. Ubiquitin-specific protease 8 (USP8) belongs to ubiquitin proteasome system and mediates the stability of E3 ligases. The anti-inflammatory effect of USP8 has been widely investigated in distinct diseases, while the role of USP8 in asthma remains elusive. Firstly, human bronchial epithelial cells (BEAS-2B) were treated with lipopolysaccharide, which reduced the cell viability of BEAS-2B and induced the secretion of lactate dehydrogenase (LDH). Moreover, the expression of USP8 was downregulated in BEAS-2B post lipopolysaccharide treatment. Secondly, overexpression of USP8 enhanced cell viability of lipopolysaccharide-treated BEAS-2B, and reduced the LDH secretion. USP8 overexpression also attenuated lipopolysaccharide-induced upregulation of TNF-α, IL-6, and IL-1β in BEAS-2B. Thirdly, lipopolysaccharide treatment promoted the expression of NLRP3 (NLR Family Pyrin Domain Containing 3), N-terminal domain of gasdermin D (GSDMD-N), caspase-1, IL-1β, and IL-18 in BEAS-2B, which was inhibited by USP8 overexpression. Lastly, USP8 overexpression decreased the phosphorylation of NF-κB, while it increased the phosphorylation of PI3K and AKT in lipopolysaccharide-treated BEAS-2B. In conclusion, USP8 inhibited lipopolysaccharide-triggered inflammation and pyroptosis in human bronchial epithelial cells by activating PI3K/AKT signaling and inhibiting NF-κB signaling pathway.
哮喘以气道上皮细胞功能障碍为特征，被视为一种气道慢性炎症性疾病。泛素特异性蛋白酶8（USP8）属于泛素蛋白酶体系统，介导E3连接酶的稳定性。USP8的抗炎作用已在多种不同疾病中得到广泛研究，但其在哮喘中的作用仍不清楚。首先，用脂多糖处理人支气管上皮细胞（BEAS-2B），这降低了BEAS-2B的细胞活力并诱导乳酸脱氢酶（LDH）的分泌。此外，脂多糖处理后BEAS-2B中USP8的表达下调。其次，USP8的过表达增强了脂多糖处理的BEAS-2B的细胞活力，并减少了LDH的分泌。USP8的过表达还减弱了脂多糖诱导的BEAS-2B中TNF-α、IL-6和IL-1β的上调。第三，脂多糖处理促进了BEAS-2B中NLRP3（含NLR家族pyrin结构域3）、gasdermin D的N端结构域（GSDMD-N）、半胱天冬酶-1、IL-1β和IL-18的表达，而USP8的过表达抑制了这些表达。最后，USP8的过表达降低了NF-κB的磷酸化，而在脂多糖处理的BEAS-2B中增加了PI3K和AKT的磷酸化。总之，USP8通过激活PI3K/AKT信号并抑制NF-κB信号通路，抑制脂多糖触发的人支气管上皮细胞炎症和焦亡。
