Adhesive Properties and Inflammatory Potential of Citrullinated Myelin Basic Protein Peptide 45–89

Abstract

Deimination of arginyl residue of myelin basic protein (MBP) reduces cationicity of MBP and impedes the normal myelin membrane assembly. Less ordered structure of MBP is more susceptible to proteolytic attack that may lead to the release of highly immunogenic deiminated peptides into extracellular milieu. We have studied the association of peptides 45-89 derived from citrullinated MBP (C8 isomer) and phosphorylated MBP (C3 isomer) with the myelin lipids in a model membrane system using optical waveguide lightmode spectrometry. The analysis of association/dissociation kinetics to planar lipids under controlled hydrodynamic conditions has shown that MBP 45-89 peptide from citrullinated C8 isomer is less effectively adsorbed on the lipid membrane, than peptide from phosphorylated C3 isomer and packing densities for phosphorylated 45-89 MBP peptide is higher than for citrullinated forms. On the other hand, our results shown that continuous (24 h) exposure of mixed oligodendrocyte/microglial cells to peptides 45-89 from MBP-C8 induces apoptosis via mitochondrial pathway. In addition, peptides 45-89 stimulated the secretion of nitric oxide from microglial cells via induction of iNOS and decreased the level of the inhibitory protein IkB, indicating involvement of the transcription factor NF-kB in these processes. Our results suggest that some citrullinated peptides, initially released from oligodendrocytes, might activate microglia, which produces reactive nitrogen species and generates in turn fatal feedbacks that kill oligodendrocytes.

Efficacy of different intensity of aquatic exercise in enhancing remyelination and neuronal plasticity using cuprizone model in male Wistar rats

“…39 Myelin basic protein is important for maintaining the structural stability of myelin and is an essential component for efficient nerve conduction. 43 Prior regular exercise has been shown to have a positive impact on reducing demyelination and axonal damage in the spinal cord of EAE animals, as well as on dendritic damage in striatal neurons. 44 A decrease in MBP expression reflects the demyelinating status of MS. 45 The present study showed a decrease in MBP levels in the Cup group, and, conversely, improved MBP expression in Cup+MP and Cn+Cup+HIE gropus.…”

Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment

“…Aberrant citrullination has been detected in myelin proteins (ie, MBP), 148 and is proposed to contribute to myelin sheath instability and increased proteolysis with release of immunogenic peptides, 149,150 eventually leading to oligodendrocyte apoptosis. 151 …”

Citrullinated isomer of myelin basic protein can induce inflammatory responses in astrocytes

“…Nitrite accumulation was used as an index of NO production and inflammatory activation in general. The assay was carried out as in our previous works ( Shanshiashvili et al, 2012 ). The widely used bacterial antigen LPS (a proinflammatory agent) was used to evaluate the inflammation rate in cultured astrocytes.…”