Transitory loss of glia and the subsequent modulation in inflammatory cytokines/chemokines regulate paracellular claudin-5 expression in endothelial cells

• Gliotoxin induced imbalance between pro-/anti-inflammatory cytokines/chemokines.
• Changes in cytokine/chemokine expression occurred as BBB integrity was lost.
• In vitro, TNF-α, IL-6 and MCP-1 induced loss of paracellular claudin-5 expression.
• TNF-α and IL-6 effects were mediated through the PI3K pathway.
• IL-10 attenuated TNF-α induced loss of claudin-5 expression.

Signaling mechanisms involved in regulating blood–brain barrier (BBB) integrity during central nervous system (CNS) inflammation remain unclear. We show that an imbalance between pro-/anti-inflammatory cytokines/chemokines alters claudin-5 expression. In vivo, gliotoxin-induced changes in glial populations and an imbalance between pro-/anti-inflammatory cytokine/chemokine expression occurred as BBB integrity was compromised. The balance was restored as BBB integrity was re-established. In vitro, TNF-α, IL-6, and MCP-1 induced paracellular claudin-5 expression loss. TNF-α- and IL-6- effects were mediated through the PI3K pathway and IL-10 attenuated TNF-α's effect. This study shows that pro-/anti-inflammatory modulators play a critical role in BBB integrity during CNS inflammation.

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