Amplification and propagation of interleukin-1? signaling by murine brain endothelial and glial cells.

ABSTRACT: During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1? (IL-1?) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1? with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1? and (2) examine the interactions between different IL-1?-responsive cell types in various co-culture combinations.We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL-1?, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests.IL-1? increased inflammatory gene expression and NF-?B activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1? elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-?B in isolated microglia, these cells were more robustly activated by IL-1? when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1?, because the application of IL-1? to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1? exposure.Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and glia. We propose that the brain's innate immune response differs depending upon which side of the blood-brain barrier the inflammatory stimulus arises, thus allowing the brain to respond differently to central vs. peripheral inflammatory insults.

SUBMITTER: Krasnow SM 

PROVIDER: S-EPMC5494131 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature