Differential expression of the CD14/TLR4 complex and inflammatory signaling molecules following i.c.v. administration...

The CD14/toll-like receptor 4 (TLR4) complex plays a vital role in initiating lipopolysaccharide (LPS) signaling during inflammation. In this study, we assessed innate immune responses and inflammatory transmission in the rat brain following intracerebroventricular (i.c.v.) administration of LPS. I.c.v. LPS induced the widespread increase in CD14 mRNA but did not change levels of TLR4 transcription in the brain. An increase in TLR4 immunoreactivity, coincident with cell death, leukocyte infiltration and neural tissue damage, was found in the meninges, choroid plexus and ventricular ependyma. In addition to CD14, rapid increases in gene expression of IkappaBalpha, IL-1beta, and TNF-alpha occurred along the meninges and ventricular ependyma. The response was most intense along the borders of the brain and declined in intensity in the adjacent periventricular areas and cerebral cortex. In the brain parenchyma, increased TLR4 immunoreactivity was confined to the vasculature and neighboring tissues along with strong vascular expression of IkappaBalpha and mPGES-1. These results suggest involvement of TLR4 in both brain inflammation and neural tissue injury and support the hypothesis that local diffusion and vascular transmission of inflammatory molecules are two major routes for developing inflammation in the brain.