title: Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils.
abstract: Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b(+) cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS.
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Barthelmes
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany.
authors.forename: Anika Männer
authors.initials: AM
authors.lastname: de Bazo
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Schmitz
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Mayer
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60590 Frankfurt/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, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Henke
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 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, 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: D000328:Adult; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D023063:Receptors, Interleukin-8B; D016179:Granulocyte Colony-Stimulating Factor; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase
keywords: CXCR2; Ceramide synthase 2; Experimental autoimmune encephalomyelitis; Granulocyte-colony stimulating factor; Multiple sclerosis