Regulation of Gap Junctional Communication by a Pro-Inflammatory Cytokine in Cystic Fibrosis Transmembrane Conductance Regulator-Expressing but Not Cystic Fibrosis Airway Cells

Chanson, Marc; Berclaz, Pierre-Yves; Scerri, Isabelle; Dudez, Tecla; Wernke-Dollries, Kara; Pizurki, L.; Pavirani, Andréa; Fiedler, Michael; Suter, Susanne

doi:10.1016/s0002-9440(10)64133-8

Cited by 62 publications

(68 citation statements)

References 54 publications

(60 reference statements)

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“…In the experimental brain abscess model which has been developed in our laboratory using S. aureus, we have shown that IL-1β and TNF-α play critical roles in CNS pathology . Interestingly, these same proinflammatory cytokines have recently been reported by others to exert dramatic effects on glial homocellular GJC (Chanson et al, 2001;Duffy et al, 2000;Faustmann et al, 2003;John et al, 1999). Based upon this evidence, we propose that proinflammatory mediators released by S. aureus-activated astrocytes in developing brain abscesses may be capable of modulating the nature and extent of GJC, with changes initiated in the proximity of the lesion and consequently extending to affect the surrounding astrocytic syncytial network.…”

Section: Introductionsupporting

confidence: 75%

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Esen

Shuffield

Syed

et al. 2006

Glia

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Gap junctions establish direct intercellular conduits between adjacent cells and are formed by the hexameric organization of protein subunits called connexins (Cx). It is unknown whether the proinflammatory milieu that ensues during CNS infection with S. aureus, one of the main etiologic agents of brain abscess in humans, is capable of eliciting regional changes in astrocyte homocellular gap junction communication (GJC) and, by extension, influencing neuron homeostasis at sites distant from the primary focus of infection. Here we investigated the effects of S. aureus and its cell wall product peptidoglycan (PGN) on Cx43, Cx30, and Cx26 expression, the main Cx isoforms found in astrocytes. Both bacterial stimuli led to a time-dependent decrease in Cx43 and Cx30 expression; however, Cx26 levels were elevated following bacterial exposure. Functional examination of dye coupling, as revealed by single-cell microinjections of Lucifer yellow, demonstrated that both S. aureus and PGN inhibited astrocyte GJC. Inhibition of protein synthesis with cyclohexamide (CHX) revealed that S. aureus directly modulates, in part, Cx43 and Cx30 expression, whereas Cx26 levels appear to be regulated by a factor(s) that requires de novo protein production; however, CHX did not alter the inhibitory effects of S. aureus on astrocyte GJC. The p38 MAPK inhibitor SB202190 was capable of partially restoring the S. aureus-mediated decrease in astrocyte GJC to that of unstimulated cells, suggesting the involvement of p38 MAPK-dependent pathway(s). These findings could have important implications for limiting the long-term detrimental effects of abscess formation in the brain which may include seizures and cognitive deficits.

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Section: Introductionsupporting

confidence: 75%

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Esen

Shuffield

Syed

et al. 2006

Glia

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“…Decreased expression of gap junction proteins (Cx43, 40, -37, and -32) and decreased gap junction communication were observed in various in vitro cell systems after exposure to proinflammatory cytokines (28). The observed changes in RNAs mediating cell adhesion and increased ex- pression of IL-1␤ seen in the CFTR(Ϫ) mice are consistent with findings that in the absence of CFTR, IL-1␤ and TNF-␣ failed to inhibit cell communication via gap junctions.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Adaptation to Cystic Fibrosis Transmembrane Conductance Regulator Deficiency

Xu¹,

Clark²,

Aronow³

et al. 2003

Journal of Biological Chemistry

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Cystic fibrosis, the most commonly inherited lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). To identify genomic responses to the presence or absence of CFTR in pulmonary tissues in vivo, microarray analyses of lung mRNAs were performed on whole lung tissue from mice lacking (CFTR(؊)) or expressing mouse CFTR (CFTR(؉)). Whereas the histology of lungs from CFTR(؊) and CFTR(؉) mice was indistinguishable, statistically significant increases in the relative abundance of 29 and decreases in 25 RNAs were identified by RNA microarray analysis. Of RNAs whose expression was consistently altered by the absence of CFTR, functional classes of genes influencing gene transcription, inflammation, intracellular trafficking, signal transduction, and ion transport were identified. RNAs encoding the transcription factor CCAAT enhancer-binding protein (CEBP) ␦ and interleukin (IL) 1␤, both known to regulate CFTR expression, were induced, perhaps indicating adaptation to the lack of CFTR. RNAs mediating lung inflammation including calgranulin-S100 family members, IL-1␤ and IL-4, were increased. Likewise, expression of several membrane transport proteins that interact directly with CFTR were increased, suggesting that CFTR-protein complexes initiate genomic responses. Absence of CFTR influenced the expression of genes modulating diverse pulmonary cell functions that may ameliorate or contribute to the pathogenesis of CF.

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“…The resulting gap junctions directly connect the cytosol of the coupled cells, allowing the exchange of ions, nutrients, and secondary messengers for the maintenance of tissue homeostasis (17). In the context of innate immunity, gap junction communication has been shown to be regulated by pathogen associated stimuli such as LPS and peptidoglycans, and secreted proinflammatory cytokines such as TNF␣, IL1␤, and IFN␥ (18,19). However, the relative contributions of contact-dependent and contact-independent communication in the establishment of host defenses have not been explored.…”

mentioning

confidence: 99%

DNA-triggered innate immune responses are propagated by gap junction communication

Patel

King

Casali

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cells respond to infection by sensing pathogens and communicating danger signals to noninfected neighbors; however, little is known about this complex spatiotemporal process. Here we show that activation of the innate immune system by double-stranded DNA (dsDNA) triggers intercellular communication through a gap junctiondependent signaling pathway, recruiting colonies of cells to collectively secrete antiviral and inflammatory cytokines for the propagation of danger signals across the tissue at large. By using live-cell imaging of a stable IRF3-sensitive GFP reporter, we demonstrate that dsDNA sensing leads to multicellular colonies of IRF3-activated cells that express the majority of secreted cytokines, including IFN␤ and TNF␣. Inhibiting gap junctions decreases dsDNA-induced IRF3 activation, cytokine production, and the resulting tissue-wide antiviral state, indicating that this immune response propagation pathway lies upstream of the paracrine action of secreted cytokines and may represent a host-derived mechanism for evading viral antiinterferon strategies.innate immunity ͉ IRF ͉ TLR ͉ interferon

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Regulation of Gap Junctional Communication by a Pro-Inflammatory Cytokine in Cystic Fibrosis Transmembrane Conductance Regulator-Expressing but Not Cystic Fibrosis Airway Cells

Abstract: Airway inflammation is orchestrated by cell-cell inter

Cited by 62 publications

References 54 publications

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Transcriptional Adaptation to Cystic Fibrosis Transmembrane Conductance Regulator Deficiency

DNA-triggered innate immune responses are propagated by gap junction communication

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