Mechanisms of high fat diet-induced loss of resistance to contact hypersensitivity in TLR2/4-deficient mice

• Applicant: Professor Dr. Stefan Martin
• Subject Area: Dermatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552697892

Low molecular, protein-reactive organic chemicals and metal ions can induce T cell-mediated allergic contact dermatitis. We have shown in the mouse contact hypersensitivity (CHS) model that the underlying essential skin inflammation is triggered by activation of the innate immune system (TLR2/4, NLRP3 inflammasome) and cellular stress responses (reactive oxygen species (ROS) production, ATP release, Unfolded Protein Response (UPR)). Interestingly, TLR2/4-deficient mice are resistant to CHS but lose their resistance at approximately 20 weeks of age. This correlates with an increase in adipose tissue, which could lead to a sub-threshold inflammation. We have now shown that feeding of 4-week old TLR2/4 mice for 4 weeks with a high fat diet (HFD) also results in the loss of resistance to CHS. In the planned project we will investigate the mechanisms of inflammation induced by (HFD), mainly based on saturated fatty acids. According to our working hypothesis, saturated fatty acids induce a TLR2/4-independent bypass to generate an inflammatory milieu that reduces the threshold for the induction of CHS far enough to allow for compensation of the TLR2/4 deficiency. This project will investigate the impact of HFD, saturated fatty acids and adipose tissue on skin barrier function, immune cells and on the microbiome to identify the alternative mechanism of inflammation that enables CHS induction. This will give new insights regarding the impact of diet on immunity and inflammatory processes. In addition, our project will reveal new mechanism-based therapeutic approaches for inflammatory (skin) diseases and point out potentialstrategies for compensating immune deficiencies by influencing inflammatory mechanisms via diet.

• DFG Programme: Research Grants