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Circulating exosomes in sepsis induce PD-1 expression in macrophages and promote Th17 differentiation

Year: 2025

Type: article

Abstract: BACKGROUND: Sepsis induces complex immunological responses; however, the role of circulating exosomes in regulating macrophage function and T-cell responses remains unknown. This study examined the effects of sepsis-derived exosomes on macrophages and their subsequent T-cell differentiation. MATERIALS AND METHODS: A cecal ligation and puncture (CLP) model was used to induce sepsis in C57BL/6 mice. Exosomes were isolated from the blood of septic (CLP-exo) and sham-operated (Control-exo) mice. Their effects on macrophage proliferation, polarization, and phagocytic function were assessed in vitro . T-cell responses were evaluated through co-culture experiments with CLP-exo-treated or Control-exo-treated macrophages and in vivo studies. RESULTS: CLP-exo inhibited macrophage proliferation, induced apoptosis, and suppressed M2 polarization. Phagocytic function was impaired and accompanied by increased PD-1 expression. Co-culture of T cells with CLP-exo-treated macrophages activated the KLF4 pathway and increased Th17-related cytokine expression. In vivo , PD-1 expression in CLP-exo-treated macrophages was associated with enhanced T-cell differentiation toward the Th17 subtype in blood. PCR array analysis revealed the activation of multiple T-cell-related genes, including Csf2, IL-2, IL-4, STAT4, and STAT6. CONCLUSION: Sepsis-derived exosomes induced PD-1 expression in macrophages and promoted Th17 differentiation, revealing a novel mechanism of immune dysregulation in sepsis. These findings provide new insights into immune dysregulation in sepsis pathophysiology.

Source: International Journal of Surgery

DOI: 10.1097/js9.0000000000003651