Postmortem homeostatic maintenance with three stepwise pH progressions in the stratum corneum of the skin

Abstract Stratum corneum (SC), the outermost skin layer comprising dead keratinocytes (corneocytes), plays a vital role in skin barrier function and maintains its thickness by shedding corneocytes, although mechanisms safeguarding SC homeostasis remained unclear. Ex vivo studies reported that monotonous neutral-to-acidic pH distribution exists in the SC; however, we present by intravital SC-pH imaging at the single-corneocyte resolution that corneocytes undergo postmortem differentiation and develop three-tiered zonation: the lower-moderately acidic, middle-acidic, and upper-neutral zones. The upper SC-pH zone possesses acclimation capacity, changing its pH according to the external environment and having a neutral pH owing to skin microbiota under steady-state. The middle SC-pH zone represents the acid mantle layer, providing a defensive barrier against pathogens. Mathematical model incorporating the three-tiered zonation simulated the high catalytic activity of kallikrein-related peptidases on the SC surface, resulting in proper corneocyte shedding. Thus, the three-tiered SC-pH zonation provides a crucial platform for maintaining SC homeostasis.