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<p>Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule that negatively regulates T-cell activation and serves as a characteristic marker of exhausted T cells in bacterial and viral infections. In this study, we found that <i>Enterococcus faecalis (E. faecalis)</i> infection modulated macrophage immune function under inflammatory conditions by upregulating PD-L1 expression. The aim of this study was to investigate the effect and potential regulatory mechanisms of <i>E. faecalis</i> and its virulence factor lipoteichoic acid (LTA) on the expression of PD-L1 in macrophages. RAW264.7 cells were treated with <i>E. faecalis</i> or LTA, respectively. Cellular immunofluorescence staining, flow cytometry, quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were employed to assess the expression of PD-L1 and endoplasmic reticulum (ER) stress-related proteins, including inositol-requiring enzyme 1 α (IRE1 α) and X-box binding protein 1 (XBP1), in macrophages. Following inhibition of the IRE1 α/XBP1 pathway and treatment with <i>E. faecalis</i>, qRT-PCR, flow cytometry, and WB were performed to detect the expression of PD-L1 and XBP1. Macrophage apoptosis was quantified by flow cytometry. Toll-like receptor 2 (TLR2) was knocked down using small interfering RNA (siRNA), and the expression of PD-L1, IRE1 α, and XBP1 in TLR2-silenced macrophages stimulated by <i>E. faecalis</i> was evaluated by qRT-PCR and WB. Statistical significance was analyzed using the Mann–Whitney test and Kruskal–Wallis test. The results demonstrated that <i>E. faecalis</i> and LTA significantly enhanced the expression of PD-L1, IRE1 α, and XBP1s in macrophages. Inhibition of the IRE1 α/XBP1 pathway reduced XBP1s and PD-L1 expression as well as apoptosis in <i>E. faecalis</i>-stimulated macrophages. TLR2 silencing decreased PD-L1, IRE1 α, and XBP1s expression levels in <i>E. faecalis</i>-stimulated macrophages. These findings reveal a novel mechanism by which <i>E. faecalis</i> induces persistent apical periodontitis and provide a foundation for further exploration of immune checkpoint molecules in the pathogenesis and treatment of this disease.</p>

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Enterococcus faecalis and lipoteichoic acid up-regulated PD-L1 of macrophage through TLR and IRE1 α/XBP1 signaling axis

  • 期刊论文

  • 发表日期：

    2025年9月13日

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  • Yanling Yang,
  • Runze Liu,
  • Qing Sun,
  • Zhuo Chen,
  • Wei Fan

摘要

Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule that negatively regulates T-cell activation and serves as a characteristic marker of exhausted T cells in bacterial and viral infections. In this study, we found that Enterococcus faecalis (E. faecalis) infection modulated macrophage immune function under inflammatory conditions by upregulating PD-L1 expression. The aim of this study was to investigate the effect and potential regulatory mechanisms of E. faecalis and its virulence factor lipoteichoic acid (LTA) on the expression of PD-L1 in macrophages. RAW264.7 cells were treated with E. faecalis or LTA, respectively. Cellular immunofluorescence staining, flow cytometry, quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were employed to assess the expression of PD-L1 and endoplasmic reticulum (ER) stress-related proteins, including inositol-requiring enzyme 1 α (IRE1 α) and X-box binding protein 1 (XBP1), in macrophages. Following inhibition of the IRE1 α/XBP1 pathway and treatment with E. faecalis, qRT-PCR, flow cytometry, and WB were performed to detect the expression of PD-L1 and XBP1. Macrophage apoptosis was quantified by flow cytometry. Toll-like receptor 2 (TLR2) was knocked down using small interfering RNA (siRNA), and the expression of PD-L1, IRE1 α, and XBP1 in TLR2-silenced macrophages stimulated by E. faecalis was evaluated by qRT-PCR and WB. Statistical significance was analyzed using the Mann–Whitney test and Kruskal–Wallis test. The results demonstrated that E. faecalis and LTA significantly enhanced the expression of PD-L1, IRE1 α, and XBP1s in macrophages. Inhibition of the IRE1 α/XBP1 pathway reduced XBP1s and PD-L1 expression as well as apoptosis in E. faecalis-stimulated macrophages. TLR2 silencing decreased PD-L1, IRE1 α, and XBP1s expression levels in E. faecalis-stimulated macrophages. These findings reveal a novel mechanism by which E. faecalis induces persistent apical periodontitis and provide a foundation for further exploration of immune checkpoint molecules in the pathogenesis and treatment of this disease.