Infection and sensitization reveal stimulus-specific immune remodeling in aged skin.

UNLABELLED: Aging is associated with progressive declines in skin barrier integrity and immune protection, contributing to increased susceptibility to bacterial and viral skin infections in older adults. However, how aged skin senses and responds to infection or barrier disruption remains poorly defined. Here, we characterized the age-associated cutaneous immune response to epicutaneous Staphylococcus (S.) aureus infection and ovalbumin-induced sensitization in mouse models. Bulk RNA-seq of infected tissue showed that transcriptional variation was primarily driven by infection, not age, suggesting that aged skin retains a broadly inducible response to microbial challenge. In contrast, microneedle patch (MNP) sampling of skin interstitial fluid, which provides cellular resolution, revealed age-dependent differences in local immune dynamics after S. aureus infection, including altered magnitude and kinetics of cellular recruitment, such as an attenuated cutaneous T cell response in older mice. MNP profiling further showed that ovalbumin sensitization elicited a localized immune program distinct from the S. aureus response, which was incompletely reflected in systemic measurements. Together, these data demonstrate that aging does not uniformly impair cutaneous immunity but instead is a context-dependent remodeling of local tissue immune dynamics.

ONE-LINE SUMMARY: Aging does not uniformly attenuate cutaneous immunity but instead remodels tissue-resident immune dynamics in a context-dependent manner depending on the skin challenge.