# Myelin Basic Protein Post-Translational Modifications Orchestrate Astrocyte Regulatory Networks

## TL;DR

This study shows how different forms of myelin basic protein affect astrocyte behavior, influencing inflammation and repair in multiple sclerosis.

## Contribution

The paper reveals novel insights into how MBP modifications drive distinct astrocyte responses through cytokine, metabolic, and epigenetic pathways.

## Key findings

- C1 MBP upregulates LXR and reduces DNA methylation, promoting immune regulation and repair.
- C8 MBP induces a strong pro-inflammatory astrocyte phenotype with elevated cytokines like IL-1β and TNF-α.
- Modified MBP isomers elicit distinct astrocyte responses, suggesting potential therapeutic strategies for MS.

## Abstract

Multiple sclerosis (MS) pathogenesis involves not only immune-mediated myelin injury but also glial responses. We examined how three charge isomers of myelin basic protein (MBP)—native (C1), phosphorylated (C4), and citrullinated (C8)—modulate rat astrocytes. Cytokines were quantified and grouped (pro/anti-inflammatory, chemotactic, neurotrophic, angiogenic, tissue remodeling), and regulatory markers assessed. C1 strongly upregulated the lipid-sensing receptor LXR, and reduced global DNA methylation; C4 moderately enhanced LXR; C8 failed to activate LXR or alter methylation. Functionally, C1 attenuated IL-1β, IL-6 and GM-CSF while increasing IL-10 and certain chemokines. C4 elicited an intermediate pattern, inducing CX3CL1 (fractalkine), CCL20, VEGF-A and TIMP-1 with minor effects on classical cytokines. In contrast, C8 triggered a robust pro-inflammatory phenotype, increasing IL-1α/β, TNF-α and GM-CSF, with higher IL-10, fractalkine, CCL20, VEGF-A and TIMP-1. All isomers suppressed IFN-γ, IL-4 and CNTF. These data indicate that MBP post-translational modifications drive distinct astrocyte phenotypes through integrated cytokine, metabolic and epigenetic pathways: C1 favors immune regulation and repair, C4 blends inflammatory and reparative cues, and C8 amplifies neuroinflammation. Understanding how modified MBP shapes astrocyte behavior provides mechanistic insight into lesion evolution in MS and suggests astrocyte-directed strategies to modulate neuroinflammation and promote remyelination.