Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2...

Area of Science:

• Immunology
• Microbiology
• Dermatology

Background:

• Diabetic foot ulcers (DFUs) often feature impaired healing, recurrent Staphylococcus aureus infections, and persistent inflammation.
• Perforin-2 is an innate immune molecule crucial for combating intracellular bacteria and limiting S. aureus infections in mice.

Purpose of the Study:

• To investigate the role of perforin-2 suppression in intracellular S. aureus accumulation within the epidermis of DFUs.
• To determine the impact of S. aureus-induced pyroptosis on DFU healing and inflammation.

Main Methods:

• Examined intracellular S. aureus presence in DFU epidermis and correlated it with perforin-2 levels.
• Utilized perforin-2 deficient mice to corroborate findings on S. aureus infection and immune response.
• Conducted a 4-week longitudinal clinical study in DFU patients to assess pyroptosis markers (AIM2 inflammasome, ASC-pyroptosome, IL-1β) in relation to healing outcomes.

Main Results:

• Marked suppression of perforin-2 in DFUs led to intracellular S. aureus accumulation in the epidermis, even without overt infection signs.
• Epidermal S. aureus triggered AIM2 inflammasome activation and pyroptosis, a process confirmed in perforin-2 deficient mice.
• Nonhealing DFUs exhibited increased AIM2 inflammasome and ASC-pyroptosome activity, along with elevated IL-1β levels, compared to healing DFUs.

Conclusions:

• Perforin-2 deficiency contributes to intracellular S. aureus colonization in DFUs.
• S. aureus-induced pyroptosis, mediated by the AIM2 inflammasome, plays a significant role in nonhealing DFUs.
• Targeting perforin-2 suppression and pyroptosis pathways may offer new therapeutic strategies for improving DFU healing and reducing inflammation.