Staphylococcus Aureus Vesicles Impair Cutaneous Wound Healing Through p38 MAPK-MerTK Cleavage-Mediated Inhibition of Macrophage Efferocytosis

Background Introduction

Staphylococcus aureus (S. aureus) is one of the primary pathogens causing chronic wound infections, particularly in diabetic patients, with an infection rate as high as 65%. One of the reasons chronic wounds fail to heal is the inhibition of macrophage efferocytosis, the process by which macrophages clear apoptotic cells, which is crucial for inflammation resolution and tissue repair. However, the mechanism by which S. aureus influences efferocytosis through its secreted vesicles (S. aureus vesicles, SAVs), thereby delaying wound healing, remains unclear.

This study aims to elucidate the role of SAVs in wound healing, particularly how they regulate macrophage efferocytosis to affect wound repair. Through this research, the authors hope to provide new targets and strategies for the treatment of chronic wounds.

Source of the Paper

This paper was co-authored by Jiaxin Ou, Kangxin Li, and others, with the research team coming from multiple institutions, including Southern Medical University, the First Affiliated Hospital of Zhengzhou University, and the Guangdong Academy of Sciences. The paper was published in 2025 in the journal Cell Communication and Signaling, titled “Staphylococcus aureus vesicles impair cutaneous wound healing through p38 MAPK-MerTK cleavage-mediated inhibition of macrophage efferocytosis.”

Research Process and Results

1. Isolation and Characterization of SAVs

The study first isolated bacterial extracellular vesicles (BEVs) from wound secretions of 41 trauma patients. Using ultracentrifugation and iodixanol density gradient centrifugation, the researchers successfully isolated SAVs and characterized their morphology and size using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The results showed that SAVs had a diameter of 100-150 nm and exhibited a typical bilayer membrane structure. Additionally, Western blot (WB) analysis confirmed the presence of S. aureus-specific proteins (e.g., Staphylococcal protein A, SPA) in SAVs.

2. Impact of SAVs on Wound Healing

To investigate the effect of SAVs on wound healing, the researchers conducted experiments in a mouse model. By creating full-thickness skin wounds on the backs of mice and topically applying SAVs, the researchers found that SAVs significantly delayed the wound healing process. Compared to the control group, SAVs-treated mice exhibited larger wound areas, reduced epithelialization, and more pronounced inflammatory cell infiltration. Similar results were observed in a diabetic mouse model, indicating that SAVs also inhibit wound healing in diabetic conditions.

3. Effect of SAVs on Macrophage Efferocytosis

The researchers further explored how SAVs affect macrophage efferocytosis. Through in vitro experiments, they found that SAVs significantly inhibited the ability of macrophages to engulf apoptotic cells but had no significant effect on bacterial phagocytosis. This result suggests that SAVs specifically inhibit macrophage efferocytosis rather than overall phagocytic function. Additionally, using flow cytometry and confocal microscopy, the researchers observed that SAVs-treated macrophages exhibited a significantly reduced rate of apoptotic cell engulfment.

4. SAVs Inhibit Efferocytosis via the TLR2-MyD88-p38 MAPK Signaling Pathway

To uncover the molecular mechanism by which SAVs inhibit efferocytosis, the researchers analyzed the impact of SAVs on macrophage signaling pathways. The results showed that SAVs activated the TLR2-MyD88-p38 MAPK signaling pathway, regulating the expression of several efferocytosis-related receptor genes. Notably, SAVs promoted the cleavage and shedding of Mer tyrosine kinase (MerTK), a key receptor for macrophage efferocytosis. By using a p38 MAPK-specific inhibitor (e.g., losmapimod), the researchers successfully reversed the inhibition of efferocytosis by SAVs and accelerated wound healing.

5. Role of MerTK Cleavage in SAVs-Mediated Delayed Wound Healing

The researchers further validated the critical role of MerTK in SAVs-mediated delayed wound healing. By knocking down MerTK expression using siRNA, they found that MerTK-deficient macrophages exhibited significant defects in efferocytosis. Moreover, transplanting MerTK-knockdown macrophages to wound sites resulted in markedly delayed wound healing. These findings indicate that SAVs induce MerTK cleavage, inhibit macrophage efferocytosis, and ultimately delay wound healing.

Conclusions and Significance

This study revealed that S. aureus vesicles (SAVs) activate the TLR2-MyD88-p38 MAPK signaling pathway, induce MerTK cleavage, and thereby inhibit macrophage efferocytosis, ultimately leading to delayed wound healing. This discovery not only highlights the important role of SAVs in chronic wound healing but also provides new therapeutic targets for treating chronic wounds infected with S. aureus. In particular, the application of p38 MAPK inhibitors (e.g., losmapimod) may become an effective treatment strategy.

Research Highlights

1. First Confirmation of SAVs in Wounds: This study is the first to isolate and characterize SAVs from trauma patients’ wounds, revealing their significant role in wound healing.
2. Unveiling a New Mechanism of SAVs Inhibiting Efferocytosis: Through the TLR2-MyD88-p38 MAPK signaling pathway, SAVs induce MerTK cleavage, thereby inhibiting macrophage efferocytosis.
3. Proposing New Therapeutic Strategies: The application of p38 MAPK inhibitors can reverse the inhibition of efferocytosis by SAVs and accelerate wound healing, offering new insights for the treatment of chronic wounds.

Additional Valuable Information

The study also found that SAVs not only inhibit macrophage efferocytosis but also promote the release of inflammatory factors, further exacerbating wound inflammation. This finding provides a new perspective on the multifaceted role of SAVs in chronic wounds.

Through systematic experimental design and in-depth data analysis, this study elucidates the critical role of SAVs in wound healing and provides a new theoretical foundation and potential therapeutic strategies for the treatment of chronic wounds.