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Role of salt accumulation in the skin for neuroinflammatory processes in multiple sclerosis

Dreher, J;

Background: Multiple sclerosis (MS) is a chronic inflammatory disorder of the cen- tral nervous system (CNS) with a variety of neurological symptoms. It is most likely caused by autoreactive T cells that get activated in the periphery and then migrate to the CNS, leading to an inflammatory response and thus to neurodegeneration. The most com- mon animal model replicating this disease is experimental autoimmune encephalomyeli- tis (EAE), either caused by external immunization, or by introducing a myelon specific transgenic T cell receptor (TCR) (2D2 mouse), which leads to spontaneous development of EAE. Both T helper 1 (TH1) and TH17 cells, as well as antigen presenting cells (APC) are involved in the pathomechanisms of EAE. Next to genetic factors, environmental fac- tors also play a role for the development of MS and dietary habits in particular have come into focus. High-salt conditions induce highly pathogenic TH17 cells and aggravate the course of EAE by a pathway involving certain ”salt related” genes. In the context of hypertension, it has been shown that the skin acts as a storage compartment for salt and high-salt conditions lead to lymphangiogenesis in the skin via vascular endothelial growth factor C (VEGF-C). With salt levels in the skin rising indepently of the diet during EAE, this thesis investigated a possible role of the skin for inflammatory processes during MS. Methods: The occurence of T cells and APCs and the expression of salt related genes in the skin of mice was analyzed in active EAE and the 2D2 model via quanti- tative real-time polymerase chain reaction (qRT-PCR), flow cytometry and immunofluo- rescence staining. Additionally, markers for the lymphatic system were examined in the skin of both animal models via qRT-PCR and visualized via immunofluorescence stain- ing. Some immune cell specific and salt related genes were also analyzed in the skin of mice after a high-salt diet. Results: EAE is accompanied by infiltration of different immune cells in the skin already during the priming phase of the disease. Likewise, salt related genes are expressed at higher frequency. The same results were seen in the 2D2 model, excluding effects only caused by the subcutaneous immunization. Lymphatic markers are upregulated early during EAE and correlate with lymphangiogenesis in the skin. A high-salt diet further promotes the upregulation of VEGF-C and immune cell specific genes. Conclusions: The skin may participate in the inflammatory processes during MS and EAE, possibly by acting as a site of activation for immune cells. Along this line, lym- phangiogenesis via upregulation of VEGF-C possibly promotes the migration of activated 1 immune cells to the CNS. The storage of salt in the skin and the higher expression of salt related genes correlate with neuroinflammation and render the skin a potential organ of interest for further sudies on risk factors for MS.