IL-1β Regulates Blood-Brain Barrier Permeability via Reactivation of the Hypoxia-Angiogenesis Program

Abstract

Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1β, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1β induced the expression of genes favoring vessel plasticity, including HIF-1α and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1α and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1β in the brain induced astrocytic expression of HIF-1α, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1β-induced HIF-1α in its regulation. These results suggest that IL-1β contributes to BBB permeability in MS via reactivation of the HIF–VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.

VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown

“…Recently, we investigated potential links between astrocyte reactivity and BBB breakdown. Compatible with reports from other groups, our results implicated the transcription factor hypoxia-inducible factor-1␣ and its effector VEGF-A in these events (16). VEGF-A is the most important angiogenic factor in the developing CNS (17,18) and a potent inducer of BBB disruption in adults (19,20).…”

“…Its signal-transducing receptor Flk-1/VEGFR2 is expressed by BMVECs (16), and homozygous Flk-1/VEGFR2 -/-mice exhibit a similar phenotype to that of VEGF-A mutants and die in utero (26). Mice homozygous for loss of the non-signal-transducing receptor Flt-1/VEGFR1 show excessive disorganized endothelium and are also nonviable (27).…”

“…2D). Immunoblotting for CLN-3, CLN-5, CLN-12, and OCLN showed that CLN-5 and OCLN were both down-regulated by VEGF-A, an angiogenic factor implicated as an inducer of BBB disruption (16)(17)(18)(19)(20) (Fig. 2 A).…”

“…VEGF-A is the most important angiogenic factor in the developing CNS (17,18) and a potent inducer of BBB disruption in adults (19,20). Studies including our own have localized VEGF-A to reactive astrocytes in inflammatory CNS lesions (16), but the mechanisms underlying its effects on the BBB remain unknown.…”

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

“…Although we detected only moderate increases in pro-inflammatory cytokine levels, the long term effects of chronic endothelial activation combined with low-level production of pro-inflammatory cytokines likely culminates in reduced vascular integrity with detrimental consequences. Indeed inflammatory mediators such as IL-1β, TNFα and IL-6 have been shown to have a prominent role in blood-brain barrier disruption (Abbott, 2000;Argaw et al, 2006). Though the mechanisms by which they act remain largely unclear, it has been suggested that IL-1β affects paracellular permeability while TNFα increases transcellular permeability (Abbott, 2000).…”