A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Spinal Cord Periplaques from Progressive Multiple Sclerosis Patients.

ABSTRACT

We previously reported that, in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis and low-grade inflammation. However, transcriptomic analyses did not allow providing a comprehensive view of molecular events in astrocytes vs. oligodendrocytes. Here, we re-assessed our transcriptomic data and performed co-expression analyses to characterize astrocyte vs. oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related co-expression module whose central hub was the astrocyte gene Cx43/GJA1 (connexin-43, also named gap junction protein α-1). Such a module comprised GFAP (glial fibrillary acidic protein) and a unique set of transcripts forming a TGFB/SMAD1/SMAD2 (transforming growth factor ß/SMAD family member 1/SMAD family member 2) genomic signature. Partial demyelination was characterized by a co-expression network whose central hub was the oligodendrocyte gene NDRG1 (N-myc downstream regulated 1), a gene previously shown to be specifically silenced in the normal-appearing white matter (NAWM) of MS patients. Surprisingly, besides myelin genes, the NDRG1 co-expression module comprised a highly significant number of translation/elongation-related genes. To identify a putative cause of NDRG1 downregulation in periplaques, we then sought to identify the cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach, we found five candidate immune-related genes whose upregulation associated with NDRG1 downregulation TGFB1(transforming growth factor ß 1), PDGFC (platelet derived growth factor C), IL17D (interleukin 17D), IL33 (interleukin 33), and IL12A (interleukin 12A). From these results, we propose that, in the spinal cord periplaques of progressive MS patients, TGFB1 may limit acute inflammation but concurrently induce astrocytosis and an alteration of the translation/elongation of myelin genes in oligodendrocytes.