Mechanisms of age-dependent loss of resistance to allergic contact dermatitis in mice with innate immune system defects

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Allergic contact dermatitis (ACD) is an inflammatory skin disease that is caused by protein-reactive low molecular weight chemicals, also called haptens. The prevalence of ACD is high and steadily increasing, and it is one of the most important occupation-related skin diseases. We have previously shown in the mouse contact hypersensitivity (CHS) model that contact allergens trigger an innate inflammatory immune response that requires IL-12Rb2, TLR2 and TLR4 as well as the P2X7R-mediated activation of the NLRP3 inflammasome and IL-1b. Mice deficient for TLR2/4, TLR4/IL-12Rb2 or P2X7R, NLRP3 or IL-1R are resistant to CHS. However, all of these mouse strains become fully susceptible at around 18 weeks of age and older. This age-dependent loss of resistance to CHS is the topic of the current project. Our investigations focus on the analysis of 1) the skin barrier function and 2) innate inflammatory and stress responses and their relation to the antigen-specific T cell response. Based on our preliminary data our working hypothesis is: the lack of innate signaling pathways disturbs immune homeostasis including skin barrier function. This leads to low-level inflammation, in part due to age-related increase in visceral and, most importantly, subcutaneous adipose tissue. As a result, susceptibility to CHS is acquired. This involves alternative proinflammatory pathways, e.g. tissue stress and damage responses. This project will provide new insights into the relationship between the innate immune system, adipose tissue, stress responses as well as their role in genotype- and age-dependent changes in immune homeostasis and immune responsiveness.