Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival

The immune evasion and prolonged survival of Staphylococcus aureus (S. aureus) within macrophages are key factors contributing to the difficulty in curing osteomyelitis. Although macrophages play a vital role as innate immune cells, the mechanisms by which S. aureus survives within them and suppresses host immune functions remain incompletely understood.

This study employed confocal microscopy, flow cytometry, ELISA, and siRNA technology to assess the survival capacity of S. aureus within macrophages and the impact of inflammatory cytokines on its persistence. Proteomics was used to investigate the potential mechanisms and differential proteins involved in S. aureus intracellular survival. Additionally, confocal microscopy, flow cytometry, Mdivi-1 intervention, and Western blot were utilized to validate the role of mitophagy in supporting S. aureus survival. The study further explored how the HDAC11/IL10 axis enhances mitophagy to promote intracellular S. aureus survival by using HDAC11 overexpression, siRNA, and rapamycin intervention combined with confocal microscopy and flow cytometry.

The findings demonstrated that IL10 promotes mitophagy to clear mitochondrial reactive oxygen species (mtROS), thereby enhancing the intracellular survival of S. aureus within macrophages. Additionally, we discovered that the transcriptional repressor of IL10, HDAC11, was significantly downregulated during S. aureus infection. Overexpression of HDAC11 and the use of the autophagy activator rapamycin further validated that the HDAC11/IL10 axis regulates mitophagy via the mTOR pathway, which is essential for supporting S. aureus intracellular survival.

This study reveals that S. aureus enhances IL10 production by inhibiting HDAC11, thereby promoting mitophagy and mtROS clearance, which supports its survival within macrophages. These findings offer new insights into the intracellular survival mechanisms of S. aureus and provide potential therapeutic approaches for the clinical management of osteomyelitis.