TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands

Abstract

In multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord (SC) functions slowly deteriorate beyond age 40. We previously showed that in the SC of these patients, large areas of incomplete demyelination extend distance away from plaque borders and are characterized by a unique progliotic TGFB1 (Transforming Growth Factor Beta 1) genomic signature. Here, we attempted to determine whether region- and age-specific physiological parameters could promote the progression of SC periplaques in MS patients beyond age 40. An analysis of transcriptomics databases showed that, under physiological conditions, a set of 10 homeobox (HOX) genes are highly significantly overexpressed in the human SC as compared to distinct brain regions. Among these HOX genes, a survey of the human proteome showed that only HOXA5 encodes a protein which interacts with a member of the TGF-beta signaling pathway, namely SMAD1 (SMAD family member 1). Moreover, HOXA5 was previously found to promote the TGF-beta pathway. Interestingly, SMAD1 is also a protein partner of the androgen receptor (AR) and an unsupervised analysis of gene ontology terms indicates that the AR pathway antagonizes the TGF-beta/SMAD pathway. Retrieval of promoter analysis data further confirmed that AR negatively regulates the transcription of several members of the TGF-beta/SMAD pathway. On this basis, we propose that in progressive MS patients, the physiological SC overexpression of HOXA5 combined with the age-dependent decline in AR ligands may favor the slow progression of TGFB1-mediated gliosis. Potential therapeutic implications are discussed.

TGF-β Isoforms and Receptors: A Gene Expression Analysis in Multiple Sclerosis Patients and Normal Individuals

“…Thus, the study of TGF-β isoforms and their receptors expression may be useful in determining different responses to the immunomodulatory as well as combinatory therapies. Curiously, TGF-β isoforms are important due to their conservation among vertebrates and their different roles in a variety of human diseases including tissue brosis, cancer and MS [15]. CNS degeneration and in ammation are important causes of demyelination in MS [16].…”

“…Mechanistically, TGF-β signals are generally initiated through binding this factor to the heterodimer complex, composed of type I and II transmembrane receptor serine/threonine kinase, transforming growth factor-β receptor 1 (TGF-β-R1) and TGFβ-R2 [13]. Thus far, several functions have been determined for TGF-β in MS pathogenesis, including 1) suppressing the immune responses, 2) inhibiting T cells, B cells as well as many other cells, 3) inducing the production of regulatory T cells (Treg), 4) repressing leukocyte adhesion to endothelium, 5) downregulation of adhesion molecules, and 6) sustaining a state of immune tolerance [14,15].…”

The Demonstration of an Aqp4/Tgf-Beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis

“…Indeed, previous neuropathological studies indicated that spinal cord lesions in MS progressive forms tend to be less inflammatory than their brain counterparts [21,22]. While TGFB1-mediated inhibition of acute inflammation in the spinal cord might be favored by the regionalized expression of the homeobox gene HOXA5 [14], an additional explanation, not exclusive from the former, could be that spinal cord astrocytes might be more prone to an engagement of the AQP4/TGFB1 pathway, as compared to brain astrocytes. In this regard, it should be kept in mind that, although AQP4 is expressed on astrocytes throughout the central nervous system (CNS), AQP4-expressing spinal cord astrocytes are by far the main targets of anti-AQP4 antibodies in NMO patients.…”

“…In the spinal cord of patients suffering from primary progressive or secondary progressive MS, we demonstrated the existence of large areas of periplaque astrocytosis, which extend distance away from plaque border. Such areas of tissue remodeling are characterized by an up-regulation of AQP4 [11] and a progliotic TGFB1 molecular signature [12][13][14]. We proposed that the chronic overexpression of TGFB1, while efficiently containing acute inflammation in MS spinal cords, may promote astrocytosis, partial demyelination and low grade chronic inflammation via at least two main mechanisms: (i) the astrocytic synthesis of profibrotic extracellular matrix proteins [15] and (ii) a direct inhibitory effect of TGFB1 on both myelin synthesis [13] and oligodendrogenesis [16].…”

“…Along this line, under conditions of acute neuronal insult, the engagement of the angiotensin II receptor type 1 on murine astrocytes is mandatory to contain the influx of blood leucocytes through the blood brain barrier [33]. Finally, in the context of progressive MS, inhibitors of the angiotensin converting enzyme were proposed to be of therapeutic utility as off the shelf commercially-available TGFB1 inhibitors [12][13][14]16]. Altogether, these findings clearly urge to assess the molecular links between AQP4, AGT and TGFB1 in human astrocytes.…”