Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Watanabe, Mitsuru; Kitajima, Masaki; Yamasaki, Ryo; Koyama, Jun; Takeuchi, Hideyuki; Matsushita, Takuya; Suzumura, Akio; Kira, Jun Ichi

doi:10.1038/srep38387

Cited by 39 publications

(37 citation statements)

References 59 publications

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“…Reduction of astrocytic Cx43 mRNA levels occurred after treating astrocyte/microglia cocultures but not astrocyte-rich cultures, with interferon (IFN)γ or IL-17, implying that microglia were responsible for this reduction. The authors depicted an IFNγ-mediated microglial release of IL-1β as the causal mechanism (Watanabe et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer’s Disease

et al. 2020

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Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyteoligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aβ deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyteastrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aβ toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer’s Disease

et al. 2020

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“…Cx43 exists in both mature and immature astrocytes, while Cx30 is expressed only in mature astrocytes ( 31 – 33 ), thus gliotic scar astrocytes show an upregulation of Cx43 but no detectable changes of Cx30 ( 23 ). Similarly, cultured astrocytes express detectable levels of Cx43 but not Cx30, although they can express Cx30 after very long term culture ( 33 , 34 ). These features of Cx30 make it difficult to study its dynamics and roles in inflammatory demyelination, and therefore there have been few studies of Cx30 in EAE.…”

Section: Introductionmentioning

confidence: 99%

Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia

Yamasaki

et al. 2018

Front. Immunol.

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Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35–55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.

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“…Finally, we confirmed that Th1 cell‐conditioned media, which contained a high concentration of IFNγ, reduced Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell‐derived IFNγ activates microglia to release IL‐1β that downregulates Cx43 gap junctions in astrocytes …”

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confidence: 88%

“…Because it is widely accepted that autoimmune T cells are involved in the pathogenesis of MS, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, and that this process contributes to MS lesion extension. We investigated whether CD4 + T cells influence Cx43 protein levels in astrocytes using a primary glial cell culture system …”

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confidence: 99%

Relationship between Th1 cells and astrocytic connexin 43 gap junctions in multiple sclerosis

Watanabe

Yamasaki

Kira

2017

Clinical & Exp Neuroim

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Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Cited by 39 publications

References 59 publications

Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer’s Disease

Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer’s Disease

Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia

Relationship between Th1 cells and astrocytic connexin 43 gap junctions in multiple sclerosis

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