title: Exacerbation of experimental autoimmune encephalomyelitis in ceramide synthase 6 knockout mice is associated with enhanced activation/migration of neutrophils.
abstract: Ceramides are mediators of inflammatory processes. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that CerS6 mRNA expression was upregulated 15-fold in peripheral blood leukocytes before the onset of EAE symptoms. In peripheral blood leukocytes from MS patients, a 3.9-fold upregulation was found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in peripheral blood leucocytes exacerbated the progression of clinical symptoms in EAE mice. This was associated with enhanced leukocyte, predominantly neutrophil infiltration and enhanced demyelination in the lumbar spinal cord of EAE mice. Interferon-gamma/tumor necrosis factor alpha (IFN-γ/TNF-α) and granulocyte colony-stimulating factor (G-CSF) both drive EAE development and induce expression of the integrin CD11b and the chemokine receptor C-X-C motif chemokine receptor 2 (CXCR2), and we found they also induce CerS6 expression. In vivo, the genetic deletion of CerS6 enhanced the activation/migration of neutrophils, as reflected by an enhanced upregulation of CD11b and CXCR2. In vitro, the genetic deletion of CerS6 enhanced the activation status of IFN-γ/TNF-α-stimulated neutrophils, as shown by increased expression of nitric oxide and CD11b and an increased adhesion capacity. In G-CSF-stimulated neutrophils, the migration status was enhanced, as reflected by an elevated level of CXCR2 and an increased migration capacity. These data suggest that CerS6/C16-Cer mediates feedback regulation by inhibiting the formation of CD11b and CXCR2, which are induced either by IFN-γ/TNF-α or by G-CSF, respectively. We conclude that CerS6/C16-Cer mediates anti-inflammatory effects during the development of EAE and MS possibly by suppressing the migration and deactivation of neutrophils.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.affiliation: Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ebel
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Mayer
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Barthelmes
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Tafferner
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulshöfer
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Henke
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Anika Männer
authors.initials: AM
authors.lastname: de Bazo
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Frankfurt/Main, Germany.
authors.forename: Susanne
authors.identifier: http://orcid.org/0000-0001-5035-2504
authors.initials: S
authors.lastname: Schiffmann
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D023063:Receptors, Interleukin-8B; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; C506123:CERS6 protein, human; C584439:CERS6 protein, mouse; D051049:Sphingosine N-Acyltransferase
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