LB1714 Increased epidermal penetration in aged skin modulates systemic inflammation

Systemic inflammation, associated with impaired epidermal barrier function, increases starting in middle age. However, transepidermal water loss (TEWL), the traditional measure of “inside-out” barrier function, remains intact in middle-aged and aged skin. We hypothesized that an additional source of age-related inflammation is a defective barrier to outside agents (“outside-in”). We first compared epidermal permeability to outside agents in untreated newborn vs. aged human epidermis, using a previously validated fluorescent tracer, Ca2+ Green. Permeability, as quantified by penetration volume, was 2-3x higher in aged skin. Since occlusion does not increase inflammation in young skin but increases penetration of agents on the surface of the stratum corneum (SC), we hypothesized that using occlusion to increase penetration through a defective barrier in aged skin would induce inflammation in middle-aged (12 mos) but not young (8-12 weeks) mice. Occlusion decreased SC hydration but did not change TEWL or the immune cell profiles in both young and aged mice. Occlusion increased serum IL-1 beta and IL-6, both known to be derived from epidermis, to a much greater extent in middle-aged mice and significantly enhanced Ca2+ Green permeability in middle-aged but not young mice. Occlusion did not increase serum TNF-alpha, consistent with the minimal changes seen in immune parameters. Finally, we demonstrated that larger but more widely spaced, experimentally induced barrier defects that mimic those seen with decreased hydration lead to increased outside-in penetration without increasing TEWL. These findings suggest that an “outside-in” mechanism, linked to hydration defects, might induce systemic inflammation derived from aging epidermis.