Interleukin‐1β‐induced BBB dysfunction involves decreased claudin‐5 protein expression and is dependent on non‐muscle myosin light chain kinase

Abstract

Aberrant elevation in the pro‐inflammatory cytokine interleukin‐1β (IL‐1β) contributes to neuroinflammatory diseases. Blood‐brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation, and it is known that IL‐1β directly induces BBB hyperpermeability, but the mechanisms remain unclear. Claudin‐5 (Cldn5) is a tight junction protein expressed at endothelial cell‐to‐cell contacts and is critical for maintaining BBB integrity. Non‐muscle myosin light chain kinase (nmMLCK) is a key regulator involved in endothelial permeability, and IL‐1β has been shown to modulate nmMLCK in intestinal epithelium. Considering these factors, we tested the hypothesis that IL‐1β decreases Cldn5 expression to induce BBB hyperpermeability in an nmMLCK dependent manner. Treating brain microvascular endothelial cells (BMVEC) with IL‐1β decreased trans‐endothelial electrical resistance (TER), increased monolayer permeability, and significantly decreased Cldn5 expression. However, BMVECs isolated from nmMLCK−/− mice showed attenuated TER response and unchanged Cldn5 expression upon IL‐1β challenge. In culmination, experimental autoimmune encephalomyelitis (EAE) was used as a model of neuroinflammation, and EAE‐induced BBB hyperpermeability observed in wild‐type mice was significantly reduced in nmMLCK−/− mice.Supported by NIH RO1 HL061507, GM097270, HL070752 and HL096640.