Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown

The blood brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory breakdown. Permeability of the BBB to polar molecules shows circadian variation due to rhythmic transporter expression, while basal permeability to polar molecules in non-rhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated lipopolysaccharide (LPS) injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions, then examined BBB permeability to a polar molecule. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in BBB breakdown specifically following evening LPS injection. Evening LPS led to persisting glia activation and inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion, were associated with enhanced expression of the Nos2 gene, and could be prevented in vivo by treatment with an iNOS inhibitor. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown, and reveals time-of-day as a key regulator of inflammatory BBB disruption.