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Targeting a Myeloid-Regulatory B Cell Network Reverses Immune Paralysis in Periprosthetic Joint Infections
Jintao Wu1, Shutao Zhang1, Yumin Lin2
1Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, Shanghai Jiaotong University School of Medicine, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 22, 2026
Summary
Researchers identified a novel immune suppression network in periprosthetic joint infection (PJI). Targeting this network with alendronate enhances bacterial clearance and bone repair, offering a new treatment strategy for persistent infections.
Area of Science:
- Immunology
- Microbiology
- Drug Discovery
Background:
- Periprosthetic joint infection (PJI) is characterized by a localized immunosuppressive microenvironment, leading to treatment failure and recurrence.
- Current immunomodulatory strategies to reverse this immune paralysis are limited.
- Understanding the cellular and molecular mechanisms driving immunosuppression in PJI is crucial for developing effective therapies.
Purpose of the Study:
- To delineate the immunosuppressive landscape in a murine PJI model using single-cell RNA sequencing.
- To identify key cellular players and molecular interactions responsible for immune suppression in PJI.
- To discover and validate a druggable target for reversing immune paralysis and enhancing treatment efficacy in PJI.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of murine PJI models.
- Identification and characterization of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and regulatory B cells (Bregs).
- Investigation of CXCR4 signaling pathways and drug screening for inhibitors.
- In vivo validation of alendronate in combination with antibiotics in infection models.
Main Results:
- A specific subset of CXCR4-expressing PMN-MDSCs (CXCR4+ PMN-MDSCs) was identified as a key component of the immunosuppressive network.
- CXCR4+ PMN-MDSCs interact with AHR+ and TIM1+ Bregs to maintain immune tolerance.
- Modulating CXCR4 signaling reduced immunosuppressive mediators and Breg abundance.
- Alendronate was identified as a specific inhibitor of CXCR4+ PMN-MDSCs via STAT3 signaling.
- Combination therapy with alendronate and vancomycin enhanced bacterial clearance, reversed immune paralysis, and promoted bone repair in vivo.
Conclusions:
- A druggable CXCR4+ PMN-MDSC-Breg immune tolerance network drives persistent skeletal infections.
- Alendronate represents a promising therapeutic agent for targeting this network.
- This immunomodulatory paradigm offers a translational approach to overcome treatment resistance in PJI and other persistent skeletal infections.
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