title: Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent.
abstract: Ceramides (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-γ)-induced CerS6 upregulation was amplified by 17ß-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-α). Accordingly, CerS6 and TNF-α 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-α and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-α, 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-α/TNFR2.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.affiliation: Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ebel
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Marthe-Susanna
authors.initials: MS
authors.lastname: Wegner
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Männich
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Tafferner
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schreiber
authors.affiliation: Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Gurumoorthy
authors.initials: G
authors.lastname: Krishnamoorthy
authors.affiliation: Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. Electronic address: susanne.schiffmann@med.uni-frankfurt.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D012727:Sex Characteristics; D051049:Sphingosine N-Acyltransferase / Q000096:biosynthesis*
chemical_list: C584439:CERS6 protein, mouse; D051049:Sphingosine N-Acyltransferase
keywords: 17ß-estradiol; Ceramide synthase 6; Experimental autoimmune encephalomyelitis; Interferon gamma; Multiple sclerosis; Tumor necrosis factor alpha receptor 2