Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

Allergic contact dermatitis is an important occupational and environmental disease caused by topical exposure to chemical allergens. An area of considerable interest and, in the context of hazard identification and characterization, an area of great importance is developing an understanding of the characteristics that confer on chemicals the ability to cause skin sensitization. For the successful acquisition of skin sensitization, it is necessary that a chemical must gain access to the viable epidermis, form stable immunogenic associations with host proteins, and provide the necessary stimuli for the activation, mobilization, and maturation of skin dendritic cells (DC). It is the last of these properties that is the subject of this article. The purpose here is to review the mechanisms through which skin sensitizers provide the triggers necessary for engagement of cutaneous DC. Of particular interest are the nature and function of danger signals elicited by skin sensitizing chemicals. Among the pathways considered here are those involving Toll-like receptors, C-type lectin receptors, neuropeptide receptors, prostanoid receptors, and the inflammasome. Collectively, danger signals in the skin provide a bridge between the innate and adaptive immune systems and are of pivotal importance for the initiation of cutaneous immune responses, including those to chemical allergens that result in skin sensitization.