Abstract
BackgroundUnderstanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. It is through the filter of the blood-brain barrier that the brain responds to outside influences, and the blood-brain barrier is a critical point of failure in neuroinflammation. It is important to note that this interaction is not a static response, but one that evolves over time. While current models have provided invaluable information regarding the interaction between cytokine stimulation, the blood-brain barrier, and the brain, these approaches—whether in vivo or in vitro—have often been only snapshots of this complex web of interactions.MethodsWe utilize new advances in microfluidics, organs-on-chips, and metabolomics to examine the complex relationship of inflammation and its effects on blood-brain barrier function ex vivo and the metabolic consequences of these responses and repair mechanisms. In this study, we pair a novel dual-chamber, organ-on-chip microfluidic device, the NeuroVascular Unit, with small-volume cytokine detection and mass spectrometry analysis to investigate how the blood-brain barrier responds to two different but overlapping drivers of neuroinflammation, lipopolysaccharide and a cytokine cocktail of IL-1β, TNF-α, and MCP1,2.ResultsIn this study, we show that (1) during initial exposure to lipopolysaccharide, the blood-brain barrier is compromised as expected, with increased diffusion and reduced presence of tight junctions, but that over time, the barrier is capable of at least partial recovery; (2) a cytokine cocktail also contributes to a loss of barrier function; (3) from this time-dependent cytokine activation, metabolic signature profiles can be obtained for both the brain and vascular sides of the blood-brain barrier model; and (4) collectively, we can use metabolite analysis to identify critical pathways in inflammatory response.ConclusionsTaken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0760-y) contains supplementary material, which is available to authorized users.
Highlights
Understanding blood-brain barrier responses to inflammatory stimulation is essential to understanding the effect of inflammatory stimulation on the brain
Brown et al Journal of Neuroinflammation (2016) 13:306 (Continued from previous page). Taken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure
Inflammatory signals and cell viability it has been well established that exposure to LPS induces cytokine responses [16, 32], and in the case of other organ systems that LPS exposure has been linked to reduced tight junction protein expression [17], relatively little is known about its effects on the blood-brain barrier (BBB) and how this compares to the direct cytokine exposure that LPS is supposed to induce
Summary
Understanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. Previous studies have determined that traumatic brain injuries and cancer can activate the immune system and affect the CNS [8, 9] These reports support the idea that substances created by peripheral immune responses are crossing the blood-brain barrier (BBB) and affecting CNS function. While the rodent work is compelling, it can be difficult to reconcile with human postmortem studies [15, 16] and observations made in cell culture, which seem to indicate a much more pronounced effect of LPS on the BBB [17] One limitation of these studies is that due to the high cost of sample collection from both animals and human patients, often only a single time point after a single, short-duration exposure is analyzed. In addition to LPS directly crossing the human BBB, the cytokines it induces in the vasculature that comprise the BBB certainly can cross the barrier and affect its function [20,21,22]
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