Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Papaneophytou, Christos; Georgiou, Elena; Karaiskos, Christos; Sargiannidou, Irene; Markoullis, Kyriaki; Freidin, Mona M.; Abrams, Charles K.; Kleopa, Kleopas A.

doi:10.1002/glia.23513

Cited by 28 publications

(29 citation statements)

References 79 publications

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“…This reduction is also observed in active and chronic lesions in MS, neuromyelitis optica (NMO) and Baló's disease [80]. Absence of Cx47 or Cx32 in oligodendrocytes exacerbates clinical EAE in mice associated with increased myelin loss but does not affect Cx30 and Cx43 expression in astrocytes [81]. Pathogenic mutations in Cx32 also contribute to Charcot-Marie-Tooth disease characterized by peripheral demyelination and neuropathy [80].…”

Section: Gap Junctions Connect Astrocytes and Oligodendrocytesmentioning

confidence: 99%

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Nutma

Gent

Amor

et al. 2020

Cells

121

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Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

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Section: Gap Junctions Connect Astrocytes and Oligodendrocytesmentioning

confidence: 99%

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Nutma

Gent

Amor

et al. 2020

Cells

121

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“…Several studies have also provided the role of oligodendrocyte connexins in acquired demyelinating CNS disorders, in particularMS and related experimental models [80,81]. They also appear to have a regulatory role in neuroinflammation as their absence further aggravates inflammatory demyelination [82].…”

Section: Discussionmentioning

confidence: 99%

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple Sclerosis

Navarrete¹,

García‐Martín²,

Garrido‐Rodríguez

et al. 2020

Preprint

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Background: Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR γ /CB 2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic and neurodegenerative diseases. Methods: The efficacy of EHP-101 in vivo was evaluated in two murine models of MS, the experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination models. In EAE, transcriptomic analysis was performed by RNA-Seq and qPCR, and inflammatory and myelination markers were detected by immunohistochemistry (IHC) and confocal microscopy in both models of MS. Results: EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2 % cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone-induced microglial activation, astrogliosis and reduced axonal damage. Conclusions: Our results provide evidence that EHP-101 showed potent anti-inflammatory activity, prevented demyelination and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.

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“…Specifically, Cx47 KO mice developed EAE more rapidly while the EAE phenotype was more severe in Cx47 KO mice compared with Cx32 KO mice and in turn, both connexin mutants showed more severe manifestations compared with WT mice. Moreover, pathological analysis revealed that Cx47 KO mice developed more myelin and axonal loss than did WT and Cx32KO mice [27]. Extensive microglia/ macrophage activation with increased Iba-1 immunoreactivity was observed in all EAE groups, but this inflammatory activity was significantly greater in Cx47 KO EAE mice (Figure 1).…”

Section: Oligodendrocyte Connexin Pathology In Experimental Autoimmunmentioning

confidence: 95%

“…Motivated by the genetic disorders of oligodendrocyte connexins, and prominent inflammatory changes resulting from them, recent studies have also provided insight into their role in acquired demyelinating CNS disorders, in particular, multiple sclerosis (MS) and related experimental models [23][24][25][26]. These studies revealed that oligodendrocyte connexins are not only disrupted in MS lesions and beyond, but they also appear to have a regulatory role in neuroinflammation as their absence further exacerbates inflammatory demyelination [27]. In this review, we highlight the important role of oligodendrocyte connexins, in particular, Cx32 and Cx47 in the normal function of CNS, by introducing insights from genetic and experimental demyelination models.…”

Section: Introductionmentioning

confidence: 99%

The role of oligodendrocyte gap junctions in neuroinflammation

2019

Self Cite

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Gap junctions (GJs) provide channels for direct cell-to-cell connectivity serving the homeostasis in several organs of vertebrates including the central (CNS) and peripheral (PNS) nervous systems. GJs are composed of connexins (Cx), which show a highly distinct cellular and subcellular expression pattern. Oligodendrocytes, the myelinating cells of the CNS, are characterized by extensive GJ connectivity with each other as well as with astrocytes. The main oligodendrocyte connexins forming these GJ channels are Cx47 and Cx32. The importance of these channels has been highlighted by the discovery of human diseases caused by mutations in oligodendrocyte connexins, manifesting with leukodystrophy or transient encephalopathy. Experimental models have provided further evidence that oligodendrocyte GJs are essential for CNS myelination and homeostasis, while a strong inflammatory component has been recognized in the absence of oligodendrocyte connexins. Further studies revealed that connexins are also disrupted in multiple sclerosis (MS) brain, and in experimental models of induced inflammatory demyelination. Moreover, induced demyelination was more severe and associated with higher degree of CNS inflammation in models with oligodendrocyte GJ deficiency, suggesting that disrupted connexin expression in oligodendrocytes is not only a consequence but can also drive a pro-inflammatory environment in acquired demyelinating disorders such as MS. In this review, we summarize the current insights from human disorders as well as from genetic and acquired models of demyelination related to oligodendrocyte connexins, with the remaining challenges and perspectives.

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Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Cited by 28 publications

References 79 publications

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple Sclerosis

The role of oligodendrocyte gap junctions in neuroinflammation

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