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PD-L1 Expression Is Increased in LPS-Induced Acute Respiratory Distress Syndrome by PI3K-AKT-Egr-1/C/EBPδ Signaling Pathway

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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.

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Data Availability

The data generated in the current study and material-related information are available from the authors on reasonable request.

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Funding

This work is supported by the National Natural Science Foundation of China (grant numbers 81971858 and 31400751).

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Authors and Affiliations

  1. Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, 210009, China

    Chunguang Yan, Jing Chen, Jingya Wang, Ming Luo & Jingru Tong

  2. Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital of Southeast University, Nanjing, 210009, China

    Chunguang Yan

  3. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Integrated Chinese and Western Medicine Hospital, Tianjin University, Tianjin, 300100, China

    Chunguang Yan, Botao Wang, Qi Zhang & Ximo Wang

  4. Department of Respiratory, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Xuanli Xu

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  1. Chunguang Yan
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C.Y., Q.Z., X.X., and X.W. designed the project. C.Y., J.C., B.W., J.W., M.L., and J.T. performed experiments. C.Y., Q.Z., and X.W. prepared the manuscript.

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Yan, C., Chen, J., Wang, B. et al. PD-L1 Expression Is Increased in LPS-Induced Acute Respiratory Distress Syndrome by PI3K-AKT-Egr-1/C/EBPδ Signaling Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-01988-6

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