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

Serge Nataf

doi:10.3390/ijms21031035

Abstract

The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective control of acute inflammation in the central nervous system. Such an immunomodulatory function appears to be mediated by a promotion of the transforming growth factor beta 1 (Tgfb1) pathway. Here, these results are discussed in the context of neuromyelitis optica (NMO) and multiple sclerosis (MS) progressive forms. It is proposed that NMO and progressive MS might rely on opposite molecular mechanisms involving, in NMO, an acutely-defective AQP4/TGFB1 pathway and, in progressive MS, a chronically-stimulated AQP4/TGFB1 pathway. Data supporting the involvement of angiotensin II as a molecular link between AQP4 and TGFB1 are also reviewed.

Highlights

In a recent paper, Xue et al established that under conditions of acute neuronal insult, mice knock out for aquaporin 4 (Aqp4) exhibit an impaired systemic and intra-cerebral synthesis of transforming growth factor-beta 1 (Tgfb1) [1]
Since several non-cytotoxic effects have been firmly demonstrated in astrocytes exposed to anti-Aquaporin 4 (AQP4) antibodies, it would be interesting to determine whether such autoantibodies may impact the ability of cultured human astrocytes to synthesize TGFB1
We proposed that the chronic overexpression of TGFB1, while efficiently containing acute inflammation in multiple sclerosis (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]

Summary

Introduction

Xue et al established that under conditions of acute neuronal insult, mice knock out for aquaporin 4 (Aqp4) exhibit an impaired systemic and intra-cerebral synthesis of transforming growth factor-beta 1 (Tgfb1) [1]. This mini-review/commentary is primarily intended to discuss these results in the context of two neuroinflammatory conditions affecting the spinal cord: multiple sclerosis and the anti-AQP4 autoantibody-mediated disorder neuromyelitis optica (NMO) [2]. The paper by Xue et al brings an additional experimental proof that Tgfb1 is a potent inhibitor of acute CNS inflammation [3,4] but provides the first demonstration of an Aqp4/Tgf-β1 pathway in murine astrocytes.

Results

Conclusion