We recently reported that in the spinal cord of PPMS or SPMS patients, large areas of periplaque demyelinating lesions extend distance away from plaque borders. Such lesions are characterized by a progliotic TGF-beta 1 signature accompanied by: i) a low-grade inflammatory reaction, ii) an extensive astrocytosis and iii) a process of incomplete demyelination. It was proposed that, while efficiently dampening inflammation in MS spinal cords, TGF-beta 1 could promote astrocytosis, prevent remyelination and possibly trigger alterations of myelin synthesis. In light of these findings, a re-interpretation of two large neuropathological studies performed on MS brains and spinal cords is provided here. While results from these studies clearly showed that active plaques do not display any region-specific distribution, an important point was apparently overlooked and not discussed by the authors: a significantly higher percentage of inactive plaques was found in MS spinal cords as compared to brains and, conversely, the percentage of slowly-expanding (or smoldering) lesions was significantly lower in the spinal cord as compared to the brain. These data indicate that the spinal cord environment may be more favorable to the resolution of inflammation. Downstream of the autoimmune process leading to plaque formation, region-specific mechanisms may thus drive the outcome of active plaques. While inflammation triggers tissue destruction, inflammation may also be needed for effective tissue repair and an inappropriate dampening of inflammatory events may possibly translate into a poor level of remyelination in MS spinal cords. It is proposed here that TGF-beta 1 is involved in such a brain-spinal cord dissociation of active plaques outcome.

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 comparing periplaques to adjacent normal-appearing white matter (NAWM) areas did not allow providing a comprehensive view of molecular events in astrocytes vs oligodendrocytes. Here, we re-assessed our transcriptomic data with the aim of identifying functionally-relevant co-expression networks that would reflect astrocyte vs oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related gene module comprising GFAP, the hub gene CX43/GJA1 and a set of transcripts forming a TGFB/SMAD1/SMAD2 genomic signature. Partial demyelination was characterized by a co-expression network which, besides myelin genes, comprised a highly significant number of translation/elongation-related genes. Interestingly, the main oligodendrocyte-related hub we identified was NDRG1, a gene previously shown to be specifically silenced in the NAWM of MS patients. This result indicated that NDRG1 down-regulation could be an important event in the process of periplaque partial demyelination. To establish a putative link between NDRG1 down-regulation and a cytokine/chemokine signature, we then sought to identify cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach we found 5 candidate immune-related genes whose up-regulation associated with NDRG1 down-regulation: TGFB1, PDGFC, IL-17D, IL-33, and IL-12A. From these results we propose that in the spinal cord of MS patients with progressive forms of the disease, TGFB1 may limit acute inflammation but concurrently induce astrocytosis and an alteration of oligodendrocytes terminal differentiation.