Fig. 5

The response of the brain to acute and prolonged endotoxin exposure. (1) A single systemic challenge with LPS activates peripheral innate immune cells such as monocytes (Mo) and neutrophils (PMN) via TLR4. This triggers the release of inflammatory cytokines into the circulation, activating the cerebral endothelium and perivascular macrophages (PVM) in the circumventricular organs, which then relay inflammatory signals to the brain. Following 2 consecutive challenges, inflammatory cytokine and chemokine transcripts are upregulated in the brain. This leads to a leaky blood-brain barrier and a transient recruitment of neutrophils and monocytes to the vasculature and brain parenchyma. (2) After repeated systemic exposure to LPS, endotoxin tolerance means there is little response in the peripheral immune system, but this does not appear to occur in the brain itself [13], where there continues to be increased transcription of inflammatory cytokines and chemokines. This leads to persistent infiltration by macrophages (MØ), T cells, NK cells and NK T cells. By amplifying local inflammatory responses, this sustained recruitment of peripheral leukocytes to the brain will potentiate LPS-mediated behavioural changes