Connexins in neuromyelitis optica: a link between astrocytopathy and demyelination

Abstract

Neuromyelitis optica, a rare neuroinflammatory demyelinating disease of the CNS, is characterized by the presence of specific pathogenic autoantibodies directed against the astrocytic water channel aquaporin 4 (AQP4) and is now considered as an astrocytopathy associated either with complement-dependent astrocyte death or with astrocyte dysfunction. However, the link between astrocyte dysfunction and demyelination remains unclear. We propose glial intercellular communication, supported by connexin hemichannels and gap junctions, to be involved in demyelination process in neuromyelitis optica. Using mature myelinated cultures, we demonstrate that a treatment of 1 h to 48 h with immunoglobulins purified from patients with neuromyelitis optica (NMO-IgG) is responsible for a complement independent demyelination, compared to healthy donors’ immunoglobulins (P < 0.001). In parallel, patients’ immunoglobulins induce an alteration of connexin expression characterized by a rapid loss of astrocytic connexins at the membrane followed by an increased size of gap junction plaques (+60%; P < 0.01). This was co-observed with connexin dysfunction with gap junction disruption (−57%; P < 0.001) and increased hemichannel opening (+17%; P < 0.001), associated with glutamate release. Blocking connexin 43 hemichannels with a specific peptide was able to prevent demyelination in co-treatment with patients compared to healthy donors’ immunoglobulins. By contrast, the blockade of connexin 43 gap junctions with another peptide was detrimental for myelin (myelin density −48%; P < 0.001). Overall, our results suggest that dysregulation of connexins would play a pathogenetic role in neuromyelitis optica. The further identification of mechanisms leading to connexin dysfunction and soluble factors implicated, would provide interesting therapeutic strategies for demyelinating disorders.

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

“…Another possibility that may be directly related to the expression of AQP4–IgG is the involvement of connexins, closely related to cell adhesion molecules, in the possible origin of the irregular shape of the neurospheres. The alterations observed in their shape, as well as the presence of anti-vascular endothelial IgG, or alterations in glutamate cytotoxicity, may influence the loss of oligodendrocytes and their myelinic potential [ 7 , 17 , 18 ].…”

“…An important consideration is that remyelination is thought to be limited in NMOSD, and no treatments are able to restore myelin; however, the use of drugs that may favor remyelination is being considered for the treatment of multiple sclerosis [ 13 ], and it has also been suggested that they may promote remyelination in NMOSD, as early loss of oligodendrocytes (OLG) has been reported [ 14 , 15 , 16 , 17 ]. Other authors have reported that NMO–IgG may decrease the expression of connexins and cause oligodendrocyte damage and demyelination in NMOSD [ 18 ]. For instance, clobetasol, which promotes OLG differentiation [ 19 ], has been analyzed in an in vivo NMOSD model, with promising results.…”

Spectrum of sublytic astrocytopathy in neuromyelitis optica

“… 70 AQP4-null mice appear normal neurologically but, unlike wild-type mice, their motor performance does not improve with Rotarod training. 11 Richard et al 71 reported altered expression and function of astrocytic connexins after application of NMO-IgG. As components of tripartite CNS synapses, and the anatomical basis of the connexin-sustained astroglial syncytium that regulates the flow of water and small molecules throughout the CNS, astrocytes are crucial for synaptic plasticity and cognitive function.…”

The First Case Report of Preschool-Onset SS/SLE Coexisting With NMOSD of Chinese Origin

“…Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system that is associated with serum aquaporin-4 antibodies (AQP4-IgG) directly against the AQP4 channels on the foot processes of astrocytes ( 1 ), clinically with serious optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and intractable nausea, vomiting, and hiccups induced by area postrema syndrome (APS) as the main manifestations ( 2 ). AQP4-IgG is the amplification of inflammation that mediates the damage of the blood–brain barrier (BBB), astrocyte injury, subsequent demyelination, and finally the occurrence and development of NMOSD ( 3 ). Therefore, AQP4-IgG is considered a pathogenic marker of NMOSD, and the presence of AQP4-IgG unequivocally distinguishes NMOSD from multiple sclerosis (MS) ( 4 ).…”