Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation

摘要

Activation of microglial cells in response to ischaemic injury, inflammatory and/or immune stimuli is associated with thenmarked induction of Toll-like receptor 2 (TLR2). At present, little is known about the spatial and temporal sequence ofnevents, micro-regional specificities and the potential long term role of the TLR2 response to brain injuries. To investigatenmicroglial activation/TLR2 response in real time, we generated a transgenic mouse model bearing the dual reporter systemnluciferase/green fluorescent protein under transcriptional control of a murine TLR2 promoter. In this model, transcriptionalnactivation of TLR2 was visualized in the brains of live animals using biophotonic/bioluminescence molecular imaging andna high resolution/sensitivity charged coupled device camera. It was found that TLR2 induction/microglial activation has anmarked chronic component after ischaemic injury and may last several months after the initial attack. The pro-inflammatorynresponse was not restricted to the site of ischaemic injury but was also evident in the olfactory bulb. A significant TLR2nresponse was first seen in the olfactory bulb 6 h after stroke and several hours before the increase in photon emissionnover the site of infarction. This sequence of events was further confirmed by immunohistochemistry. A similar early TLR2nresponse from olfactory bulb microglia was observed in the brain’s immune response to pathogens. We therefore proposenthat, owing to their unique situation, receiving and translating numerous inputs from the brain as well as from the environment,nolfactory bulb microglia may serve as sensors and/or modulators of brain inflammation.