Pro-inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang-(1-7).

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)-an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.

Feeding of a fat-enriched diet causes the loss of resistance to contact hypersensitivity.

BACKGROUND: Low-molecular weight chemicals or metal ions can cause allergic contact dermatitis, an inflammatory skin disease. Mice lacking Toll-like receptors 2 and 4 (TLR2/4 mice) are resistant to contact hypersensitivity (CHS). In the Western population obesity is increasing, which is known to have a proinflammatory impact. OBJECTIVES: The aim of this study was to investigate the impact of a high-fat diet (HFD) on the sensitization and elicitation of CHS. We hypothesized that a proinflammatory micromilieu can be caused by an increase in adipose tissue, which might be sufficient to break the resistance of TLR2/4 mice. METHODS: Four weeks prior to sensitization, wild-type (wt) or TLR2/4 mice were fed normal chow (NC), control diet (CD), or HFD. The effects on CHS and inflammation were analysed by measuring the ear swelling response, using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The reaction of wt mice to 2,4,6-trinitro-1-chlorobenzene (TNCB) was increased by HFD. While NC-fed TLR2/4 mice were still resistant to CHS, HFD and, unexpectedly, CD feeding broke the resistance of TLR2/4 mice to TNCB. CONCLUSIONS: These experiments suggest that the increased fat content or the different fatty acid composition of the diets increases inflammation and, therefore, the likelihood of developing CHS.