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

Abstract

BackgroundThe 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.MethodsIntracerebroventricular (ICV) administration of 10 ng of the potent pro-inflammatory cytokine interleukin-1β (IL-1β) was used as an experimental model of central nervous system cytokine production. We examined which cells respond to IL-1β in vivo via fluorescent immunohistochemistry. Using multiple transgenic mouse lines expressing Cre recombinase under the control of cell-specific promoters, we eliminated IL-1β 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-1β signaling is essential for sickness responses.ResultsEndothelial cells, microglia, ependymal cells, and astrocytes exhibit nuclear translocation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in response to IL-1β. Interfering with IL-1β signaling in microglia, endothelial cells within the parenchyma of the brain, or both did not affect sickness responses. Only mice that lacked IL-1β signaling in all endothelium including fenestrated capillaries lacked sickness responses.ConclusionsThese experiments show that IL-1β-induced sickness responses depend on intact IL-1β signaling in blood vessels and suggest that fenestrated capillaries act as a critical signaling relay between the immune and nervous systems.Trial registrationNot applicable.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0990-7) contains supplementary material, which is available to authorized users.

Circumventricular Organs and Parasite Neurotropism: Neglected Gates to the Brain?

“…The ring formed by CVOs around the third and fourth ventricles can be seen as a hub where systemic immune responses and homeostatic brain networks interact (96). These networks regulate metabolism, energy balance, neurohormonal secretion, as well as sleep, wakefulness, their alternation and other endogenous circadian rhythms.…”

Neural Mechanisms of Inflammation-Induced Fever

“…After the recognition of the “side effects” seen following in particular OVLT ablation ( Romanovsky and others 2003 ), interest in the potential role of the CVOs for eliciting fever has faded. However, a recent report comparing the febrile response in mouse lines with different patterns of deletion in brain endothelial cells of MyD88, an adaptor protein for LPS and IL-1β signaling ( Xu and others 2000 ), suggested that fenestrated capillaries in the CVOs were important for fever in response to IL-1β injected into the brain ventricles ( Knoll and others 2017 ). However, apart from differences between the mouse lines regarding MyD88 deletion in fenestrated capillaries, there were several other potential differences between these mouse lines, such as recombination efficacy in the brain endothelium and peripheral immune cells that may have influenced the results.…”

Salt-dependent hypertension and inflammation: targeting the gut–brain axis and the immune system with Brazilian green propolis

“…In addition, both intracerebroventricular and PVN injections of IL-1β produced an increase in blood pressure of normotensive Sprague-Dawley rats (Shi et al 2010). IL-1β is an interleukin produced by the innate immune system like monocytes and macrophages cells (Lopez-Castejon and Brough 2011) and is a key modulator of inflammatory responses (Knoll et al 2017). The actions of IL-1β on SAH development seems to be focused on the central nervous system, influencing sympathetic drive by indirect mechanisms that involve activation of perivascular macrophages and increase of type 2 cyclooxygenase (COX-2) expression/activity thus leading to increased production of prostaglandin E 2 (PGE 2 ) (Yu et al 2010).…”

“…Increased secretion of PGE 2 by perivascular macrophages is believed to act on neuronal pathways within the PVN to increase the sympathetic drive to cardiovascular organs such as the heart and vasculature (Yu et al 2010). IL-1β can also act on the endothelial cells of fenestrated capillaries in the brain to trigger sickness responses dependent on intact IL-1β signaling in blood vessels (Knoll et al 2017). Since fenestrated capillaries are commonly found in circumventricular organs of the brain (CVO) such as the SFO and OVLT, it might be possible that CVO-acting IL-1β also contribute to activation of neurons in the lamina terminalis, especially at endothelial cells of fenestrated capillaries at CVO (Fig.…”