Interleukin-1β signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice

Background: The physiological and behavioral symptoms of sickness, including fever, anorexia, behavioral depression, and weight loss can be both beneficial and detrimental. These sickness responses are triggered by pro-inflammatory cytokines acting on cells within the brain. Previous research demonstrates that the febrile response to peripheral insults depends upon prostaglandin production by vascular endothelial cells, but the mechanisms and specific cell type(s) responsible for other sickness responses remain unknown. The purpose of the present study was to identify which cells within the brain are required for sickness responses triggered by central nervous system inflammation. Methods: Intracerebroventricular (ICV) administration of 10 ng of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) was used as an experimental model of central nervous system cytokine production. We examined which cells respond to IL-1 beta in vivo via fluorescent immunohistochemistry. Using multiple transgenic mouse lines expressing Cre recombinase under the control of cell-specific promoters, we eliminated IL-1 beta signaling from different populations of cells. Food consumption, body weight, movement, and temperature were recorded in adult male mice and analyzed by two-factor ANOVA to determine where IL-1 beta signaling is essential for sickness responses. Results: Endothelial cells, microglia, ependymal cells, and astrocytes exhibit nuclear translocation of NF-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) in response to IL-1 beta. Interfering with IL-1 beta signaling in microglia, endothelial cells within the parenchyma of the brain, or both did not affect sickness responses. Only mice that lacked IL-1 beta signaling in all endothelium including fenestrated capillaries lacked sickness responses. Conclusions: These experiments show that IL-1 beta-induced sickness responses depend on intact IL-1 beta signaling in blood vessels and suggest that fenestrated capillaries act as a critical signaling relay between the immune and nervous systems.