CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER) stress associated NF-κB signaling

Acute lung injury (ALI) is a common clinical disorder, resulting in substantial health problems in the world. However, the molecular mechanism that contributes to ALI is still unclear. Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs, playing a critical role in regulating various cellular processes. In the study, we attempted to explore the effects of CRBN on the progression of lipopolysaccharide (LPS)-induced ALI. First, we found that CRBN expression was markedly up-regulated in lung tissues of LPS-challenged mice. Our results suggested that CRBN knockdown mice exhibited better survival rate after LPS challenge, accompanied with improved histological alterations. Further, CRBN decrease effectively ameliorated pulmonary injury by reducing lung wet/dry (W/D) ratio and protein levels, neutrophil infiltration, myeloperoxidase (MPO) and lactate dehydrogenase (LDH) levels. In addition, LPS-triggered inflammation in lung tissues was markedly alleviated in CRBN knockdown mice by reducing the pro-inflammatory cytokines through the inactivation of nuclear factor-kappa B (NF-kappa B) signaling. Moreover, CRBN knockdown mice exhibited alleviated oxidative stress by promoting nuclear factor-erythroid 2 related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) signaling. ER stress stimulated by LPS in pulmonary tissues was significantly alleviated by CRBN knockdown through reducing the expression of ER stress associated signals, including CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP), glucose-regulated protein 78 (GRP78), XBP-1, activating transcription factor (ATF)-4, ATF-6 and phosphorylated eukaryotic initiation factor 2 on Ser51 of the alpha subunit (eIF2 alpha). The protective effects of CRBN knockdown against ALI were verified in LPS-incubated human pulmonary epithelial cells. Importantly, we found that CRBN knockdown-ameliorated inflammatory response was markedly abrogated by the pre-treatment of Nrf-2 inhibitor and ER stress activator, suggesting that CRBN-regulated inflammation in ALI was partly through the meditation of reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. In conclusion, our study firstly provided a support that CRBN decrease effectively protected LPS-induced ALI against inflammatory response mainly through the repression of oxidative stress and ER stress.