Interleukin-1 beta-induced disruption of the retinal vascular barrier of the central nervous system is mediated through leukocyte recruitment and histamine

Abstract

The vascular barriers of the central nervous system form a selective cellular interface between the blood and the neural parenchyma and restrict the transfer of both molecules and hematogenous cells. During immune-mediated diseases, leukocyte infiltration becomes dramatically up-regulated and the permeability of these barriers increases, leading to edema formation. The etiology of this damage remains largely unresolved although inflammatory cytokines have been implicated in the process. The effect of the proinflammatory cytokine interleukin (IL)-1 beta on the integrity of the rat blood-retinal barrier (BRB) was investigated up to 14 days after an intravitreal injection. The permeability of the BRB was evaluated quantitatively using the low molecular weight tracer [14C]mannitol. After IL-1 beta administration, a biphasic opening of the BRB to [14C]mannitol was recorded, peaking at 4 to 8 hours and 24 to 48 hours post-injection (PI). The early disruption coincided with the appearance of both polymorphonuclear and mononuclear leukocytes within the retina. By 12 hours PI, BRB permeability had returned to control values despite a continued increase in the number of infiltrating leukocytes. The second, more pronounced increase in barrier permeability detected at 24 to 48 hours PI corresponded with maximal leukocyte infiltration. Barrier dysfunction had resolved by 72 hours, and by 7 days the leukocyte infiltrate had disappeared. The IL-1 beta-induced increase in permeability could be completely abrogated at 4 and 24 hours PI by treating the animals with the histamine H2-receptor antagonist ranitidine, which also reduced leukocyte infiltration by 47.2%. The ability of histamine to disrupt the BRB was demonstrated by intravitreal and intravascular administration, which caused a rapid and significant increase in BRB permeability. Treatment of the animals with the cyclo-oxygenase inhibitor indomethacin had no effect on IL-1 beta-induced disruption of the BRB at 4 hours PI, but by 24 hours PI a significant reduction in permeability was observed that coincided with a 75.2% reduction in the leukocyte infiltrate. The depletion of circulating leukocytes to < 2% of control levels reduced the retinal leukocyte recruitment induced by IL-1 beta by 73.0% and decreased BRB permeability at both 4 and 24 hours after IL-1 beta injection. These data demonstrate that intravitreal IL-1 beta in the rat induces a biphasic opening of the BRB that appears to be mediated through recruited leukocytes and release of the vasoactive amine histamine.