333 Disclosing the interdependence: How obesity orchestrates skin disease

Abstract

The inflammatory skin disease psoriasis is highly prevalent and relevant. This disease is often characterized by comorbidities with obesity as the most prevalent. Clinical observations clearly indicate obesity as an aggravating factor for skin inflammation in psoriasis. The aim of the study was to investigate how obesity alters skin immune responses. To this end, a obesity model was used by feeding of C57Bl/6J mice with high-fat diet (HFD, 60% fat). To investigate the effect of obesity on Th17/Th1-mediated skin inflammation, a mouse model of 2,4,6-trinitrochlorobenzene (TNCB) contact hypersensitivity (CHS) was used. Challenging sensitized mice resulted in an increased ear swelling of obese mice. Interestingly, the ear swelling of Th2-mediated CHS against fluorescein isothiocyanate (FITC) was strongly decreased. Characterization of the immune response in the skin of TNCB-challenged mice revealed a significant upregulation of IL-17 and unchanged other cytokines, among them IL-4 and IL-13, in obese mice. In draining lymph nodes, we found an increase of CD4+ and CD8+ T cells with a decrease of relative numbers of other cells, indicating that T cells were effector cells responsible for aggravation of skin inflammation by obesity. The characterization of cell phenotypes showed an increase of IL-17+TNF+ cells and IFNγ-producing CD8+ T cells. Interestingly, the elevation of T cell numbers and TNF/IL-17 production in blood occurred already before TNCB sensitization, indicating systemic inflammation promoted by obesity. Next we tested whether systemic factors, increased due to HFD, are responsible for alterations in cell phenotypes. Treatment of immune cells with serum from obese mice resulted in an enhanced production of TNF by Gr1+ cells and elevated IL-17-producing CD4+ and CD8+ cells. The incubation of T cells with serum from obese mice during different polarization conditions led to a promotion of Th1 phenotype with a marked reduction of Tregs. Taken together, our work indicates that obesity promotes skin inflammation by selective enhance of Th17/Th1 immune response.