Microglia activation influences dye coupling and Cx43 expression of the astrocytic network

Faustmann, Pedro M.; Haase, Claus G.; Romberg, Sabine; Hinkerohe, Daniel; Szlachta, Dominika; Smikalla, Dirk; Krause, Dorothee; Dermietzel, Rolf

doi:10.1002/glia.10141

Cited by 87 publications

(136 citation statements)

References 54 publications

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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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“…A source of IL-1 could be reactive astrocytes as well as activated microglia. In agreement, gap junctional communication between astrocytes is reduced by activated micloglia in cultures [121,42]. These changes in connexin expression may represent reactive gliosis or be part of adaptive processes that reduce damage or provide tolerance to subsequent ischemic episodes (preconditioning).…”

Section: Pattern Of Connexin Expression In the Adult Mammalian Brainmentioning

confidence: 73%

“…A source of IL-1 could be reactive astrocytes as well as activated microglia. Gap junctional communication between astrocytes is reduced by activated microglia in cultures [121,42].…”

Section: Pattern Of Connexin Expression In the Adult Mammalian Brainmentioning

confidence: 99%

Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue

Contreras

Sánchez

Véliz

et al. 2004

Brain Research Reviews

220

185

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Gap junction channels and hemichannels formed of connexin subunits are found in most cell types in vertebrates. Gap junctions connect cells via channels not open to the extracellular space and permit the passage of ions and molecules of ~1 kDa. Single connexin hemichannels, which are connexin hexamers, are present in the surface membrane before docking with a hemichannel in an apposed membrane. Because of their high conductance and permeability in cell-cell channels, it had been thought that connexin hemichannels remained closed until docking to form a cell-cell channel. Now it is clear that at least some hemichannels can open to allow passage of molecules between the cytoplasm and extracellular space. Here we review evidence that gap junction channels may allow intercellular diffusion of necrotic or apoptotic signals, but may also allow diffusion of ions and substances from healthy to injured cells, thereby contributing to cell survival. Moreover, opening of gap junction hemichannels may exacerbate cell injury or mediate paracrine or autocrine signaling. In addition to the cell specific features of an ischemic insult, propagation of cell damage and death within affected tissues may be affected by expression and regulation of gap junction channels and hemichannels formed by connexins.

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“…The levels of soluble factors secreted by microglia following treatment with LPS have been found to be proportional to the numbers of activated microglia cells in vitro (8,25) and in vivo (17,25). Therefore, we studied if the observed increase in the numbers of round microglia in BDVinfected mixed cultures would be associated with an enhanced release of soluble factors following LPS treatment.…”

Section: Fig 2 Lps and Hiv-tat But Not Purified Bdv Activate Microgliamentioning

confidence: 99%

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Ovanesov

Sauder

Rubin

et al. 2006

J Virol

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Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1␤, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.Borna disease virus (BDV) is a nonsegmented, negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad spectrum of warm-blooded animals (3,12,22). In neonatally infected rats, BDV causes a life-long persistent infection of the CNS with minimal signs of classical inflammatory cell infiltration (e.g., encephalitis and meningitis) and the absence of overt clinical disease. Nonetheless, neonatal BDV infection is associated with a progressive loss of granule cells in the dentate gyrus of the hippocampus, Purkinje cells in the cerebellum, and GABA-ergic neurons in the neocortex (5,16,18,45).Because BDV establishes a persistent noncytolytic infection in various cell lines and primary neurons and astrocytes in vitro (6,20,34), the mechanisms of neuronal degeneration in vivo remain unclear. Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38). Intriguingly, BDV-associated microgliosis has been found predominantly in areas of significant neuronal loss, i.e., cortex, hippocampus, and cerebellum (22,33,38,44), leading to the hypothesis that microglia activation plays a central role in BDV-associated neuronal damage (38,44).Microglia, the resident macrophage population in the brain, play a central role ...

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Microglia activation influences dye coupling and Cx43 expression of the astrocytic network

Cited by 87 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

Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

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