Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis

Zhao, Yinan; Yamasaki, Ryo; Yamaguchi, Hideyo; Nagata, Satoshi; Une, Hayato; Cui, Yiwen; Kitajima, Masaki; Nakamuta, Yuko; Iinuma, K.; Watanabe, Mitsuru; Matsushita, Takuya; Isobe, Noriko; Kira, Jun Ichi

doi:10.1073/pnas.1901294117

Cited by 36 publications

(31 citation statements)

References 34 publications

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“…Recent tissue and cell-type-specific transcriptomic studies suggest a relevant role for neurotoxic A1 astrocytes in MS pathogenesis [ 42 , 43 ]. However, the induction pattern of astrocytic A1 phenotype related genes in rodent models of the disease remains to be fully characterized.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

et al. 2020

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The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS.

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Section: Resultsmentioning

confidence: 99%

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

et al. 2020

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“…In contrast to gap junctions, which typically open under physiological conditions, undocked connexons, also termed hemichannels, have a low open probability and open in response to injury [ 10 ]. Altered hemichannel activity is associated with the pathophysiology of multiple disease states, with evidence linking altered cell-to-cell communication to increased senescence [ 54 ], inflammation [ 34 , 55 , 56 ] and fibrosis [ 18 , 19 , 20 , 21 ]. Data from our own lab demonstrate that the predominant connexin isoform in the proximal tubule (Cx43) is up-regulated in advanced CKD and correlates with elevated levels of TGFβ1 and severity of fibrosis and inflammation [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney

Squires

Price

Mouritzen

et al. 2021

IJMS

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Chronic kidney disease (CKD) is a global health problem associated with a number of comorbidities. Recent evidence implicates increased hemichannel-mediated release of adenosine triphosphate (ATP) in the progression of tubulointerstitial fibrosis, the main underlying pathology of CKD. Here, we evaluate the effect of danegaptide on blocking hemichannel-mediated changes in the expression and function of proteins associated with disease progression in tubular epithelial kidney cells. Primary human proximal tubule epithelial cells (hPTECs) were treated with the beta1 isoform of the pro-fibrotic cytokine transforming growth factor (TGFβ1) ± danegaptide. qRT-PCR and immunoblotting confirmed mRNA and protein expression, whilst a cytokine antibody array assessed the expression/secretion of proinflammatory and profibrotic cytokines. Carboxyfluorescein dye uptake and ATP biosensing measured hemichannel activity and ATP release, whilst transepithelial electrical resistance was used to assess paracellular permeability. Danegaptide negated carboxyfluorescein dye uptake and ATP release and protected against protein changes associated with tubular injury. Blocking Cx43-mediated ATP release was paralleled by partial restoration of the expression of cell cycle inhibitors, adherens and tight junction proteins and decreased paracellular permeability. Furthermore, danegaptide inhibited TGFβ1-induced changes in the expression and secretion of key adipokines, cytokines, chemokines, growth factors and interleukins. The data suggest that as a gap junction modulator and hemichannel blocker, danegaptide has potential in the future treatment of CKD.

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“…We more recently reported that Cx47 icKO mice showed marked microglial activation toward a pro‐inflammatory and injury‐response phenotype, and A1‐specific astrocytic activation in demyelinating lesions of the spinal cord. Oligodendroglia‐specific Cx47 deletion induces severe inflammation on autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation 67 …”

Section: Glial Cxs In Inflammatory Demyelination Modelsmentioning

confidence: 99%

Recent advances in understanding connexin gap junction pathology in demyelinating diseases

Kitajima

2020

Clinical & Exp Neuroim

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Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and Baló’s disease (BD) are inflammatory demyelinating diseases of the central nervous system. We previously reported that aquaporin‐4 antibody‐independent astrocytopathy can occur in heterogeneous demyelinating conditions. We focused on connexins (Cxs), which form gap junctions between astrocytes and oligodendrocytes to form the glial syncytium of the central nervous system. We investigated the pathological expression pattern of Cx43/Cx30 in astrocytes, and Cx47/Cx32 in oligodendrocytes in autopsied samples from MS, NMOSD and BD. Astrocytic Cx43 and oligodendrocytic Cx32/Cx47 were extensively diminished in both demyelinated and myelinated layers in all BD cases. Half of the NMOSD and MS cases showed preferential loss of astrocytic Cx43 in active demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte‐oligodendrocyte gap junctions were widely lost. Loss of Cx43 was frequently accompanied by distal oligodendrogliopathy, which is characterized by a preferential loss of myelin‐associated glycoprotein and apoptotic‐like oligodendrocytes. Isolated perivascular lesions in the spinal cord of NMOSD cases showed loss of aquaporin‐4 and Cx43, indicating early involvement of Cx43 in NMOSD. Neuronal and glial Cxs were affected in gray matter demyelination in MS and neurodegenerative diseases. Our findings show that Cx43 astrocytopathy and Cx47/Cx32 oligodendrogliopathy can be seen in MS, BD and NMOSD. Furthermore, the loss of astrocytic Cx43 might be associated with disease aggressiveness and distal oligodendrogliopathy in demyelinating conditions. Early disruption of glial gap junctions might disturb the glial syncytium and disrupt intercell communication, thereby inducing oligodendroglial injury and subsequent demyelination.

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Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis

Cited by 36 publications

References 34 publications

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney

Recent advances in understanding connexin gap junction pathology in demyelinating diseases

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