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

Abstract

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.

Genome-wide association study of sepsis in extremely premature infants

“…47 Downregulation of gap junction channels results from inflammation and infection. 48–51 Several pathways regulating fibroblast growth factor receptors were also significantly enriched (Supplementary Table 3), and are implicated in attachment and replication of certain pathogens. 52–55 Pathways related to gap junction channels and fibroblast growth factor receptors may play important roles in mediating respiratory and gut mucosal integrity.…”

Modulation of connexin signaling by bacterial pathogens and their toxins

“…In cultures of primary mouse astrocytes, though, both S. aureus and its peptidoglycan silence gap junction activity, a process that involves the p38 MAPK signaling cascade. At the connexin level, a decrease in mRNA and protein amounts of both Cx30 and Cx43 was observed, whereas Cx26 production became induced [169]. In a recent study, Karpuk and colleagues reported downregulated astrocyte GJIC in brain slices of mice infected with S. aureus.…”

Translational potential of astrocytes in brain disorders

“…Astroglial reactivity is also linked to activation of toll-like TLR2 type receptors (Esen et al ., 2004). Bacterial infection is also reported to down-regulate expression of connexins that form intercellular gap junctional and hence astroglial syncytia, which is regarded as a neuroprotective mechanism, limiting the spread of inflammation (Esen et al ., 2007). Astrogliotic response in the context of bacterial infection has clear defensive capacity: the neurological damage was exacerbated when S. aureus were injected in the brains of mice with the genetic deletion of GFAP (Stenzel et al ., 2004).…”