Ubiquitin-specific protease 8 inhibits lipopolysaccharide-triggered pyroptosis of human bronchial epithelial cells by regulating PI3K/AKT and NF-κB pathways.

Abstract

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.