CXCL16/CXCR6/TGF-β Feedback Loop Between M-MDSCs and Treg Inhibits Anti-Bacterial Immunity During Biofilm Infection

Area of Science:

• Immunology
• Microbiology
• Orthopedics

Background:

• Staphylococcus aureus is a primary cause of periprosthetic joint infection (PJI).
• Immunosuppression contributes to chronic S. aureus PJI, complicating treatment.
• Understanding the immunosuppressive microenvironment is crucial for PJI management.

Purpose of the Study:

• To investigate the link between the immunosuppressive biofilm milieu and S. aureus PJI outcomes.
• To identify key cellular players and molecular interactions driving immunosuppression in PJI.
• To explore potential therapeutic targets within this pathway.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of patient synovium.
• In vivo studies using a Treg-specific CXCR6 knockout PJI mouse model.
• Immunohistochemistry and clinical recurrence analysis.

Main Results:

• Expansion and heightened activity of monocyte-related myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Treg) were observed in PJI patients.
• CXCL16 upregulation in M-MDSCs and CXCR6 elevation on Treg mediate M-MDSC-Treg cross-talk.
• Interfering with CXCL16-CXCR6 signaling reduced immunosuppression and bacterial burden in a mouse model.
• High CXCR6 expression in PJI synovium correlated with poor prognosis and recurrence.

Conclusions:

• The CXCL16-CXCR6 axis is critical for Treg recruitment and activity, orchestrating immunosuppression in PJI.
• This pathway promotes biofilm persistence and contributes to poor clinical outcomes in PJI patients.
• Targeting the CXCR6 pathway presents a potential therapeutic strategy for S. aureus PJI.