Blockade of Experimental Multiple Sclerosis by Inhibition of the Acid Sphingomyelinase/Ceramide System

• Main Authors: Katrin Anne Becker, Ramona Halmer, Laura Davies, Brian D. Henry, Regan Ziobro-Henry, Yann Decker, Yang Liu, Erich Gulbins, Klaus Fassbender, Silke Walter
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2017-11-01
• Series: Neurosignals
• Subjects: Multiple sclerosis; Acid sphingomyelinase; Ceramide; Tight junctions; Experimental autoimmune encephalomyelitis
• Online Access: https://www.karger.com/Article/FullText/484621
• ISSN: 1424-862X; 1424-8638

Background: Multiple sclerosis (MS) is a severe and common autoimmune disorder of the central nervous system. Despite the availability of several novel treatment options, the disease is still poorly controlled, since the pathophysiological mechanisms are not fully understood. Methods: We tested the role of the acid sphingomyelinase/ceramide system in a model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin-oligodendrocyte glycoprotein and the development of the disease was analyzed by histology, immunological tests and clinical assessment in wildtype and acid sphingomyelinase (Asm)-deficient mice. Results: Genetic deficiency of acid sphingomyelinase (Asm) protected against clinical symptoms in EAE and markedly attenuated the characteristic detrimental neuroinflammatory response. T lymphocyte adhesion, integrity of tight junctions, blood-brain barrier disruption and subsequent intracerebral infiltration of inflammatory cells were blocked in Asm-deficient mice after immunization. This resulted in an almost complete block of the development of disease symptoms in these mice, while wildtype mice showed severe neurological symptoms typical for EAE. Conclusion: Activation of the Asm/ceramide system is a central step for the development of EAE. Our findings may serve to identify novel therapeutic strategies for MS patients.