Lymphatics-dependent modulation of the sensitization and elicitation phases of contact hypersensitivity

Allergic contact dermatitis is a common inflammatory skin disease comprising of two phases. During sensitization, immune cells are activated by exposure to various allergens, while repeated antigen exposure induces local inflammation during elicitation. Here, we utilized mouse models lacking lymphatics in different skin regions to characterize the role of lymphatics separately in the two phases, using contact hypersensitivity (CHS) as a model of the human disease. Lymphatic-deficient mice exhibited no major difference to single antigen exposure compared to controls. However, mice lacking lymphatics in both phases displayed reduced inflammation after repeated antigen exposure. Similarly, diminished immune response was observed in mice lacking lymphatics only in sensitization, while the absence of lymphatics only in the elicitation phase resulted in a more pronounced inflammatory immune response. This exaggerated inflammation is driven by neutrophils impacting regulatory T cell number. Collectively, our results demonstrate that skin lymphatics play an important but distinct role in the two phases of CHS. During sensitization lymphatics contribute to the development of the antigen-specific immunization, while in elicitation, they moderate the inflammatory response and leukocyte infiltration in a neutrophil-dependent manner. These findings underscore the need for novel therapeutic strategies targeting lymphatics in the context of allergic skin diseases.