Brain Advance Access published online on January 19, 2009
Brain, doi:10.1093/brain/awn345
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Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation
Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l’Université Laval, Québec, Canada
Correspondence to:
Dr Jasna Kriz, Faculty of Medicine, Centre de Recherche du CHUL (CHUQ), T3-67, Université Laval, 2705 Boulevard Laurier, Québec, Canada G1V 4G2 E-mail: jasna.kriz{at}crchul.ulaval.ca
Activation of microglial cells in response to ischaemic injury, inflammatory and/or immune stimuli is associated with the marked induction of Toll-like receptor 2 (TLR2). At present, little is known about the spatial and temporal sequence of events, micro-regional specificities and the potential long term role of the TLR2 response to brain injuries. To investigate microglial activation/TLR2 response in real time, we generated a transgenic mouse model bearing the dual reporter system luciferase/green fluorescent protein under transcriptional control of a murine TLR2 promoter. In this model, transcriptional activation of TLR2 was visualized in the brains of live animals using biophotonic/bioluminescence molecular imaging and a high resolution/sensitivity charged coupled device camera. It was found that TLR2 induction/microglial activation has a marked chronic component after ischaemic injury and may last several months after the initial attack. The pro-inflammatory response was not restricted to the site of ischaemic injury but was also evident in the olfactory bulb. A significant TLR2 response was first seen in the olfactory bulb 6 h after stroke and several hours before the increase in photon emission over the site of infarction. This sequence of events was further confirmed by immunohistochemistry. A similar early TLR2 response from olfactory bulb microglia was observed in the brain's immune response to pathogens. We therefore propose that, owing to their unique situation, receiving and translating numerous inputs from the brain as well as from the environment, olfactory bulb microglia may serve as sensors and/or modulators of brain inflammation.
Key Words: neuroinflammation; bioluminescence/biophotonic imaging; microglia; luciferase; reporter mouse model
Abbreviations: AcGFP, Aequorea coerulescens Green Fluorescent Protein; BAC, bacterial artificial chromosome; CCD, charged coupled device; DCX, doublecortin; DLIT, diffuse luminescent imaging tomography; GFP, green fluorescent protein; LPS, lipopolysaccharide; LUC, luciferase; OB, olfactory bulb; PAMP, pathogen-associated molecular patterns; PBS, phosphate buffered saline; PFA, paraformaldehyde; PCR, polymerase chain reaction; RT–PCR, Reverse transcriptase–polymerase chain reaction; TLR, Toll-like receptor; TNF, tumour necrosis factor; WT, wild-type
Received May 8, 2008. Revised October 27, 2008. Accepted November 20, 2008.