Abstract: P527

Type: Poster

Abstract Category: Immunomodulation / Immunosuppression

In experimental autoimmune encephalomyelitis (EAE) we observed a 15-fold upregulation of Ceramide Synthase 6 (CerS6) mRNA expression in peripheral blood leukocytes before onset of EAE symptoms. In peripheral blood leukocytes (PBL) from Multiple sclerosis (MS) patients, a 3.9-fold upregulation was found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in PBL exacerbated the progression of clinical symptoms in EAE, associated with enhanced leukocyte, predominantly neutrophil (NC) infiltration and enhanced demyelination in the lumbar spinal cord. 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 CXCR2 and we found they also induce CerS6 expression. In vivo, the genetic deletion of CerS6 enhanced the activation/migration of NC, 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 (NO) and CD11b and an increased adhesion capacity. In G-CSF18 stimulated NC, the migration status was enhanced, as reflected by an elevated level of CXCR2 and an increased migration capacity. These data suggest that CerS6 and C16-Ceramides (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 NC.

Disclosure:

Max Eberle: I have nothing to disclose

Philipp Ebel: I have nothing to disclose

Christoph Mayer received travel grants from genzyme, biogen and Merck serono and speakers honoraria from genzyme, Merck serono and biogen

Julia Barthelmes: I have nothing to disclose

Nadja Tafferner: I have nothing to disclose

Nerea Ferreiros: I have nothing to disclose

Thomas Ulshöfer: I have nothing to disclose

Marina Henke: I have nothing to disclose

Annika Männer de Bazo received travel grants from genzyme

Christian Foerch received travel grants from TEVA pharma, biogen and genzyme and speakers honoraria from genzyme and biogen

Andreas Weigert: I have nothing to disclose

Sabine Grösch: I have nothing to disclose

Gerd Geisslinger: I have nothing to disclose

Klaus Willecke: I have nothing to disclose

Susanne Schiffmann: I have nothing to disclose