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.

Machine-Learned Data Structures of Lipid Marker Serum Concentrations in Multiple Sclerosis Patients Differ from Those in Healthy Subjects

“…In line with this research, cholesterol and its turnover products have been proposed as biomarkers for MS [4]. Further classes of lipid mediators regulated in MS include sphingolipids [21], ceramides, or lysophosphatidic acids [7,8]. …”

“…Recent investigations point at several further classes of lipids that are regulated in MS. Currently, a scientific focus centers on eicosanoids including hydroxyeicosatetraenoic acids [6], ceramides, and lyosophosphatidic acids [7,8]. Along with the increasing knowledge about lipid signaling emerging from contemporary molecular research, the acquired data become increasingly complex, which is acknowledged in proposals to implement bioinformatics methods in lipid research [9,10,11].…”

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

“…The production of C16 ceramide by CerS6 inhibited neutrophil adhesion, and the expression of CXCR2. They postulated that Cers6 functions to regulate a feedback regulatory loop to inhibit migration and protects from the onset of disease (Fig 2) (Eberle et al, 2015). …”

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease

“…Female C57BL/6J mice were immunized with MOG 35−55 /CFA emulsion pertussis toxin kits (EK-2110, Hooke laboratories) according to the manufacturer’s instructions [26, 27]. Briefly, 0.1 ml MOG 35−55 /CFA emulsion was injected subcutaneously into both flanks of each mouse (0.2 ml/animal, 200 μg of MOG 35−55 peptide in each 0.2 ml dose).…”