Eberle, M.M.EberleEbel, P.P.EbelWegner, M.S.M.S.WegnerMännich, J.J.MännichTafferner, N.N.TaffernerFerreiros, N.N.FerreirosBirod, K.K.BirodSchreiber, Y.Y.SchreiberKrishnamoorthy, G.G.KrishnamoorthyWillecke, K.K.WilleckeGeisslinger, G.G.GeisslingerGrösch, S.S.GröschSchiffmann, S.S.Schiffmann2022-03-042022-03-042014https://publica.fraunhofer.de/handle/publica/23882810.1016/j.bcp.2014.08.016Ceramides (Cer) are mediators of inflammatory processes. In a chronic experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we observed a significant elevation of C16-Cer and its synthesizing enzyme, ceramide synthase(CerS)6, in the lumbar spinal cord. In the present study, we have confirmed that C16-Cer and CerS6 are also upregulated in the lumbar spinal cord in a spontaneous relapse-remitting EAE model, using SJL mice overexpressing a transgenic T cell receptor (TCR1640). CerS6 was found to be expressed in macrophages, T cells and B cells in EAE lesions. In macrophages, we demonstrated that interferon gamma (IFN-g)-induced CerS6 upregulation was amplified by 17ß-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-a). Accordingly, CerS6 and TNF-a expression was upregulated predominantly in the spinal cord in female TCR1640 mice, which usually develop the relapse-remitting form of EAE, while male TCR1640 mice showed an attenuated regulation of CerS6 and TNF-a and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-a, which is linked to neuroprotection and remyelination, was also upregulated to a greater extent during EAE in female TCR1640 mice in comparison to male TCR1640 mice. Taken together, our results confirm the upregulation of CerS6 and C16-Cer in an adjuvant-independent, physiological EAE model and further suggest an anti-inflammatory role of CerS6 in the regulation of the disease course in female TCR1640 mice via TNF-a/TNFR2.en540571572journal article