Disruption of the blood–brain barrier in collagen-induced arthritic mice

Patients with rheumatoid arthritis (RA) are at higher risk of developing pathological cardiovascular and cerebrovascular events than non-RA subjects. Vascular endothelial dysfunction is involved in the induction of cardiovascular events and this process is also observed in patients with RA. Endothelial dysfunction impairs the integrity of the blood–brain barrier (BBB); this phenomenon also underlies brain damage in cerebrovascular diseases. This study was aimed at evaluating the influence of a chronic inflammatory state on BBB integrity in RA using collagen-induced arthritis (CIA), an animal model of RA. CIA was induced by intradermal injection of type II collagen emulsified with Freund's complete adjuvant at the base of the tail of DBA/1 mice. Cerebrovascular permeability was assessed by measurement of sodium fluorescein (Na–F) content in the brains of CIA mice. The expression level of tight junction proteins was investigated by immunoblotting and immunofluorescence of occludin and zonula occludens-1 (ZO-1). Cerebrovascular permeability to Na–F in the brain was increased in CIA mice. This CIA-induced BBB hyperpermeability was more remarkable in the advanced stage than that in the persistent stage of the arthritis. The expression of occludin, but not that of ZO-1, was decreased by CIA. Our results indicate that the integrity of the BBB could be impaired in the inflammatory pathophysiology of RA.