Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src

Xie, Xi; Lan, Tian; Chang, Xiuting; Huang, Kaipeng; Huang, Juan; Wang, Shaogui; Chen, Cheng; Shen, X. Y.; Liu, Peiqing; Huang, Heqing

doi:10.1186/1478-811x-11-38

Cited by 40 publications

(33 citation statements)

References 46 publications

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“…Thus, upregulated CCL2 could play a role in the increased severity of BBB/BSCB disruption in Cx47KO mice. Interestingly, astrocytic CCL2 expression is controlled by NF‐κB (Giraud, Caron, Pham‐Dinh, Kitabgi, & Nicot, ) and by activation of stat1 (Wang et al, ), while Cx43, the major partner of Cx47 at O:A GJs (Orthmann‐Murphy et al, ), mediates NF‐κB signaling activation (Xie et al, ). Thus, loss of Cx47 and the potential dysfunction of Cx43 (Markoullis, Sargiannidou, Gardner, et al, ) may directly affect the regulation of the astrocyte activation cascade.…”

Section: Discussionmentioning

confidence: 99%

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Papaneophytou

Georgiou

Karaiskos

et al. 2018

Glia

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Gap junctions (GJs) coupling oligodendrocytes to astrocytes and to other oligodendrocytes are formed mainly by connexin47 (Cx47) and a smaller portion by connexin32 (Cx32). Mutations in both connexins cause inherited demyelinating disorders, but their expression is also disrupted in multiple sclerosis (MS). To clarify whether the loss of either Cx47 or Cx32 could modify the outcome of inflammation and myelin loss, we induced experimental autoimmune encephalomyelitis (EAE) in fully backcrossed Cx32 knockout (KO) and Cx47KO mice and compared their outcome with wild type (WT, C57BI/6 N) mice. Cx47KO EAE mice developed the most severe phenotype assessed by clinical scores and behavioral testing, followed by Cx32KO and WT mice. Cx47KO more than Cx32KO EAE mice developed more microglial activation, myelin, and axonal loss than did WT mice. Oligodendrocyte apoptosis and precursor proliferation was also higher in Cx47KO than in Cx32KO or WT EAE mice. Similarly, blood‐spinal cord barrier (BSCB) disruption and inflammatory infiltrates of macrophages, T‐ and B‐cells were more severe in Cx47KO than either Cx32KO or WT EAE groups. Finally, expression profiling revealed that several proinflammatory cytokines were higher at the peak of inflammation in the Cx47KO mice and persisted at later stages of EAE in contrast to reduction of their levels in WT EAE mice. Thus, loss of oligodendrocyte GJs aggravates BSCB disruption and inflammatory myelin loss, likely due to dysregulation of proinflammatory cytokines. This mechanism may play an important role in MS brain with reduced connexin expression, as well as in patients with inherited mutations in oligodendrocyte connexins and secondary inflammation.

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Section: Discussionmentioning

confidence: 99%

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Papaneophytou

Georgiou

Karaiskos

et al. 2018

Glia

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“…There was a strong trend (p=0.06) for RG but not CP diminishing the AUC for IkBa degradation. Since cytokine-induced c-Src levels might be higher in Cx43 deficient cells and since c-Src binds and thereby acts as a sink for IkBa (33, 34), we investigated c-Src expression in INS-1 cells exposed to cytokines in the presence or absence of RG or CP. As shown in fig.…”

Section: Resultsmentioning

confidence: 99%

The connexin 43 regulator Rotigaptide reduces cytokine-induced cell death in human islets

Ghiasi

Hansen

Christensen

et al. 2018

Preprint

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20Background: Intercellular communication mediated by cationic fluxes through the Connexin-family 21 of gap-junctions regulates glucose-stimulated insulin-secretion and beta-cell defense against 22 inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular 23 conductance in cardiac muscle-cells by prevention of dephosphorylation and thereby uncoupling of 24 Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is 25 being studied in human arrhythmias. It is unknown if RG protects beta-cell function and viability 26 against inflammatory or metabolic stress, a question of considerable translational interest for the 27 treatment of beta-cell failure in diabetes. 28Methods: Apoptosis was measured in human islets known to express Cx43, treated with RG or the 29 control peptide ZP119 and exposed to glucolipotoxicity or IL-1b + IFNg. INS-1 cells shown to lack 30 Cx43 were used to verify if RG protected human islet-cells via Cx43-coupling. To study mechanisms 31 of action of Cx43-independent effects of RG, NO, IkBa degradation, mitochondrial activity, ROS and 32 insulin mRNA levels were determined. 33Results: RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells 34 this protective effect was markedly blunted as expected, but unexpectedly RG still modestly reduced 35 apoptosis, and improved mitochondrial function, insulin-2 gene levels and accumulated insulin release. 36RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS-expression, 37 suggesting that RG blunts cytokine-induced NF-kB signaling in insulin-producing cells in a Cx43-38 independent manner.39 Conclusion: RG reduces cytokine-induced cell-death in human islets. The protective action in Cx43-40 deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-kB signaling.3 41 Highlights: 43  Rotigaptide (RG) counteracts cytokine-induced apoptosis in human islets 44  RG reduces cytokine-induced apoptosis in INS-1 cells independently of Cx43 45 Introduction: 46 By inducing beta-cell endoplasmic reticulum stress and apoptosis via the intrinsic mitochondrial 47 pathway, proinflammatory cytokines have been implicated as mediators of beta-cell failure and 48 destruction causing type 1 diabetes (T1D) and type 2 diabetes (T2D) (1). Antagonism of the action of 49 the prototypic proinflammatory cytokine interleukin-1 (IL-1) improves beta-cell function in T2D 50 patients (2), an effect sustained 39 weeks beyond cessation of the antagonism in responders (3). 51Despite a strong preclinical rationale (4) anti-IL-1 monotherapy was ineffective overall in recent-onset 52 T1D. However, IL-1 antagonism did moderate inflammation and caused a 2,5-fold higher secretory 53 function in T1D patients with intermediary beta-cell function at baseline (5, 6). Since IL-1 induced 54 beta-cell apoptosis is potentiated by other proinflammatory cytokines such as TNF, IFNg and IL-6, and 55 since anti-TNF therapy improved beta-ce...

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“…Therefore, Cx43 down-regulation may contribute to the dysfunction of the blood-retina barrier through vascular permeability in diabetic retinopathy. Though this effect is best characterized in retinal tissue, several studies have demonstrated a significant role for Cx43 in regulation of TJ proteins, such as occludin, at the BBB (Chronopoulos et al, 2010), and ZO-1 in kidney (Xie et al, 2013). …”

Section: Pericyte Dysfunctionmentioning

confidence: 99%

Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

Bogush

Heldt

Persidsky

2017

J Neuroimmune Pharmacol

120

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Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications.

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Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src

Cited by 40 publications

References 46 publications

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

The connexin 43 regulator Rotigaptide reduces cytokine-induced cell death in human islets

Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

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