Circadian skin pH gates IL-33 and remote food sensitization

Skin barrier disruption can initiate the atopic march, yet comparable injuries do not invariably trigger systemic alarmin bursts. The physiological gates determining when barrier perturbation generates an endocrine signal remain incompletely defined. We hypothesized that circadian oscillations in the acid mantle regulate the threshold for systemic interleukin-33 (IL-33) release and remote allergic sensitization. Using a transepidermal water loss (TEWL)-clamped tape-stripping model to match barrier injury independent of baseline permeability, we identified a nocturnal alarmin-competent state (Zeitgeber Time 20) characterized by higher surface pH, dehydration, and elevated serine protease activity. Despite matched TEWL loss, nocturnal neutral injury generated a larger systemic IL-33 pulse than daytime injury. Acidifying the surface during injury suppressed protease activity, improved residual TEWL recovery, and substantially reduced, but did not eliminate, systemic IL-33 release and anaphylaxis severity, with more variable effects on IgE sensitization. Recombinant IL-33 restored allergic susceptibility in acid-protected mice, while ST2 blockade suppressed sensitization despite an intact IL-33 pulse, supporting IL-33/ST2 signaling as a necessary downstream checkpoint. Circadian loss of surface acidity therefore lowers the threshold for systemic IL-33 release after microinjury and may license remote allergic priming.