Epithelial-Dermal Immune Memory: Tracking Staphylococcus aureus-Induced Trained Immunity in the Progression of Chronic Skin Inflammation

The clinical paradigm distinguishing chronic atopic dermatitis (AD) from acute bacterial infections is established by the emerging evidence which focuses on persistent innate immune memory as a central pathobiological factor mediating inflammatory skin diseases. While AD is classically defined by genetic susceptibility and epidermal barrier failure, progression of deep dermal Staphylococcus aureus invasion, which is characteristic of bacterial infections like cellulitis, implies a significant acute infectious condition resulting in significant tissue damage, which drives extensive innate immune reprogramming. Recent studies have established a bidirectional relationship between these conditions, yet the underlying molecular mechanisms remain undefined. However, trained immunity, governed by epigenetic and metabolic reprogramming, has now emerged as a critical mediator of this interaction. This review attempts to explore the molecular foundations of trained immunity as a mechanistic link between acute infectious conditions and chronic skin inflammation. The critical involvement of bacterial virulence factors and pattern recognition receptor signalling pathways, which instigate persistent innate memory, predisposes the tissue to recurrent infections and aggravated inflammatory responses. Furthermore, the persistent involvement of innate immune reprogramming in facilitating a mechanistic continuum between cellulitis and chronic dysregulation, characteristic of atopic dermatitis, is discussed. In continuum, we propose emphasising emerging therapeutic strategies targeting epigenetic checkpoints and metabolic rewiring to develop novel immunomodulatory interventions to combat infectious and inflammatory skin disorders.