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

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.

Keywords: T lymphocytes; exosomes; kruppel-like factor 4 (KLF4); macrophages; programmed cell death 1 (PD-1); sepsis.