Abstract：
The role of programmed death ligand 1 (PD-L1) has been extensively investigated in adaptive immune system. However, increasing data show that innate immune responses are also affected by the immune checkpoint molecule. It has been demonstrated that regulation of PD-L1 signaling in macrophages may be a potential therapeutic method for acute respiratory distress syndrome (ARDS). However, the PD-L1 expression pattern in local macrophages and whole lung tissues remains mysterious, hindering optimization of the potential treatment program. Therefore, we aim to determine the PD-L1 expression pattern during ARDS. Our findings show that PD-L1 levels are markedly increased in lipopolysaccharide (LPS)-stimulated lung tissues, which might be attributable to an increase in the gene expression by immune cells, including macrophages and neutrophils. In vitro experiments are performed to explore the mechanism involved in LPS-induced PD-L1 production. We find that PD-L1 generation is controlled by transcription factors early growth response 1 (Egr-1) and CCAAT/enhancer binding protein delta (C/EBPδ). Strikingly, PD-L1 production is enhanced by phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway via up-regulation of Egr-1 and C/EBPδ expressions. Additionally, we observe that expressions of Egr-1 and C/EBPδ mutually reinforce each other. Moreover, we observe that PD-L1 is protective for ARDS due to its regulatory role in macrophage-associated inflammatory response. In summary, during LPS-induced ARDS, PD-L1 expression, which is beneficial for the disease, is increased via the PI3K-AKT1-Egr-1/C/EBPδ signaling pathway, providing theoretical basis for application of methods controlling PD-L1 signaling in macrophages for ARDS treatment in clinic.
摘要：
程序性死亡配体1(PD-L1)在适应性免疫系统中的作用已被广泛研究。然而,越来越多的数据表明，先天免疫反应也受到免疫检查点分子的影响。已经证明，调节巨噬细胞中的PD-L1信号传导可能是急性呼吸窘迫综合征（ARDS）的潜在治疗方法。然而,局部巨噬细胞和整个肺组织中的PD-L1表达模式仍然神秘，阻碍潜在治疗方案的优化。因此,我们的目的是确定ARDS期间PD-L1的表达模式。我们的研究结果表明，PD-L1水平在脂多糖（LPS）刺激的肺组织中显著增加，这可能归因于免疫细胞基因表达的增加，包括巨噬细胞和中性粒细胞.进行体外实验以探索参与LPS诱导的PD-L1产生的机制。我们发现PD-L1的产生受转录因子早期生长反应1（Egr-1）和CCAAT/增强子结合蛋白δ（C/EBPδ）的控制。引人注目的是，通过上调Egr-1和C/EBPδ表达，磷酸肌醇-3激酶（PI3K）-蛋白激酶B（AKT）信号通路可增强PD-L1的产生。此外,我们观察到Egr-1和C/EBPδ的表达相互增强。此外，我们观察到PD-L1对ARDS具有保护性,因为它在巨噬细胞相关炎症反应中具有调节作用.总之,在LPS诱导的ARDS期间，PD-L1表达，这对疾病是有益的，通过PI3K-AKT1-Egr-1/C/EBPδ信号通路增加，为控制巨噬细胞PD-L1信号传导的方法在临床ARDS治疗中的应用提供理论依据。
