Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis

Abstract

The protection of the brain from blood-borne toxins, proteins, and cells is critical to the brain's normal function. Accordingly, a compromise in the blood-brain barrier (BBB) function accompanies many neurologic disorders, and is tightly associated with brain inflammatory processes initiated by both infiltrating leukocytes from the blood, and activation of glial cells. Those inflammatory processes contribute to determining the severity and prognosis of numerous neurologic disorders, and can both cause, and result from BBB dysfunction. In this review we examine the role of BBB and inflammatory responses, in particular activation of transforming grown factor β (TGFβ) signaling, in epilepsy, stroke, and Parkinson's disease.

Figure 1

Astrocytes, microglia, and leukocytes in the brain’s circulation all contribute toward breaching the BBB by NF-kB–mediated production of proinflammatory cytokines. This process is blocked by acetylcholine interacting with the alpha7 nicotinic receptor that antagonizes NF-kB activation. The production of AChE, and in particular the stress-inducible soluble AChE-R variant limits acetylcholine blockade, increasing BBB promiscuity.

Figure 2

Following BBB disruption albumin enters into the brain environment and is taken up by astrocytes, thereby activating TGFβ signaling, and eliciting inflammatory responses and astrocytic dysfunction. This, in turn, modulates neurovascular unit function and promotes epileptogenesis. Hypersynchronous epileptic activity by itself, promotes production and release of inflammatory mediators by astrocytes and microglia, which in turn compromise the BBB integrity. Inflammatory molecules produced by astrocytes and microglia (i.e., IL-1β, HMGB1) contribute to seizure onset and recurrence also by directly activating their receptors (IL-1R, TLR, RAGE) overexpressed by neurons. Autocrine effects of IL-1β, HMGB1 on astrocytes play a role in perpetuating inflammation via NF-kB–mediated transcriptional up-regulation of inflammatory genes.