A study led by Francisco J. Quintana, PhD, BWH Department of Neurology, found increased levels of the bioactive lipid lactosylceramide (LacCer) in the central nervous system in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
LacCer is synthesized by the enzyme beta-1,4-galactosyltransferase 6 (B4GALT6) in astrocytes, a type of glial cell found in the central nervous system. Astrocytes normally regulate synaptic activity and support neurons, but during central nervous system inflammation these cells control infiltration by peripheral pro-inflammatory white blood cells and regulate cells of the adaptive immune response. Given that multiple sclerosis is a central nervous system autoimmune disease involving inflammation, the researchers sought to investigate the role of astrocytes in this process.
In pre-clinical models of EAE, upregulation of B4GALT6 was observed in astrocytes, which in turn increased levels of LacCer. The LacCer then acted back upon the astrocytes to activate production of the pro-inflammatory molecule CCL-2 via the transcription factors NF-κB and IRF-1. This then led to the recruitment of pro-inflammatory white blood cells to the central nervous system, promoting inflammation and neurodegeneration. Blocking LacCer synthesis using a B4GALT6 inhibitor prevented CCL-2 production and pro-inflammatory cell recruitment to the central nervous system. Moreover, in central nervous system multiple sclerosis lesions from patients, increased B4GALT6 and LacCer were detected.
“These findings identify B4GALT6 in astrocytes as a driver of inflammation and neurodegeneration during chronic central nervous system autoimmunity,” said Quintana.
The study was published online Sept. 14, 2014 in Nature Medicine.