1024 Dissecting the molecular interdependence of skin inflammation and obesity

Abstract

Psoriasis, a chronic inflammatory skin disease, is often compromised by comorbidities with obesity being the most prevalent. Epidemiological studies clearly associate obesity with psoriasis. The aim of the present study was to investigate how obesity alters skin immune responses. To this end, an obesity model was established by feeding of male 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 a significant increase of ear swelling of obese mice with an elevation of IFNg- and IL-17-positive cells in draining lymph nodes (dLN) and an increase of IL-17, IL-21, IL-6, TNF in the serum. Th2 cytokin IL-4 was unchanged (serum) or decreased (dLN) due to HFD. Interestingly, the ear swelling of Th2-mediated CHS against fluorescein isothiocyanate (FITC) was diminished in obese mice. This suggests a selective enhancement of Th17/Th1 and a decrease of Th2 immune responses by obesity. Investigating underlying mechanisms, we found increased expression of IL-12, IFNg, TNF, IL-6, iNOS and CCL2 in the adipose tissue of obese mice. TNF, IL-6, iNOS, CCL2, IL-17, and macrophages were also significantly upregulated in TNCB-CHS skin of obese mice. On the contrary, Foxp3 and TGF-beta were downregulated. Further experiments showed that dermal gamma/delta T cells are the major source of IL-17, elevated due to obesity. Unexpectedly, the depletion of gamma/delta T cells resulted in significant elevation of ear swelling in obese mice in comparison to isotype-treated obese mice. These data demonstrate for the first time functional consequences of regulatory functions of gamma/delta T cells relevant for resolution of skin inflammation and that obesity specifically impairs this regulatory function. Taken together, obesity increases Th17/Th1-mediated psoriasis-like skin inflammation by i) increasing cutaneous macrophage recruitment and activation and by ii) impairing Tregs and regulatory gamma/delta T cells causing dysregulation and exaggeration of the immune response.