CRC TRR 128 A10:Skin-sensing of environmental factors and their impact on the development of multiple sclerosis (SFB-TR128)

Basic data for this project

Description

Besides genetic susceptibility factors, environmental and lifestyle stimuli, including diet, cigarette smoke, the commensal flora, the night length and melatonin content or the exposure to UV-B light, are known to play a role in the modulation of multiple sclerosis (MS). Interestingly, in experimental autoimmune encephalomyelitis (EAE) we have recently shown that local irradiation with UV-B light ameliorates disease perpetuation. As demonstrated in our work leading to this project, the effect was mediated by the induction of regulatory T cells (Treg), which efficiently suppressed pathogenic TH1 and TH17 cells finally resulting in reduced inflammatory foci and less demyelinated areas in the central nervous system (CNS) from myelin oligodendrocyte glycoprotein (MOG)-immunized and UV-B-irradiated mice compared to non-irradiated controls. In addition to directly inducing Treg, UV‑B irradiation of the skin up-regulates the release of melanocortins, such as the neuropeptide alpha-melanocyte-stimulating hormone (α‑MSH). In line with this we demonstrated in preliminary work that short-term treatment with α-MSH ameliorated ongoing EAE due to the induction of tolerogenic dendritic cells (DC) and Treg in the periphery, which inhibited the activation of encephalitogenic T cells. Thus, our data strengthen the hypothesis that environmental factors, such as UV-B light, which are sensed in the skin, modulate CNS inflammation. Besides up-regulating the release of α-MSH, UV-B irradiation of the skin contributes to the activation of vitamin D and the generation of tryptophan dimers like 6‑formylindolo[3,2‑b]carbazole (FICZ). Of note, MS is associated with lower levels of serum 25‑hydroxyvitamin D3 (25-OHD3; the usual measure of vitamin D). FICZ on the other hand acts as endogenous ligand of the aryl hydrocarbon receptor (AhR), a transcription factor frequently suggested as a sensor of environmental stimuli. Thus, lifestyle factors like UV-B, known to control the prevalence and perpetuation of MS, are sensed at epithelial barrier tissues such as the skin and exert its effects via different pathways including interfering with melanocortin and vitamin D signaling or tryptophan metabolism. Hence, this project aims to investigate how skin-sensing of UV-B light modulates disease initiation and perpetuation in mouse models of MS as well as in MS patients. Based on the various mechanisms by which UV-B light transmits its biological effects, three central aims shall be addressed: 1. Characterizing the relevance of α-MSH signaling for sensing the lifestyle-factor UV-B light. 2. Elucidating UV-B light-induced vitamin D-dependent and vitamin D-independent mechanisms for disease modulation. 3. Scrutinizing the role of AhR ligands involved in the transmission of environmental stimuli sensed in the skin. For aim 1 a small, nested proof-of-concept (POC) study in humans will be carried out in collaboration with project Z.