In Vivo Imaging of Microglia Cells Activated by LPS-Induced Systemic Inflammation in Mouse

Introduction: The role of microglia cells in the pathogenesis of inflammations and chronic neurodegenerative disorders in the central nervous system (CNS) is an active research field in recent years. The ramified form of microglia cells is activated via inflammation markers (e.g. IL-1b, TNF-alpha). The activated form of microglia cells as a key player of the innate immune system in the CNS present MHC II and release antiinflammatory agents. The activation status of the microglial benzodiazepine (BZD) receptor system could be used to monitor the process of neuroinflammation. Methods: Healthy (n=6) and LPS induced inflamed (n=4) C57BL/6 mice were used. The activation of the microglia cells was induced by systemic injection of 0.3 g/bw kg lipopolysaccharide (LPS) 5h before the in vivo measurements. We used NanoSPECT/CT Plus and nanoScan PET/MRI (Mediso Ltd, Hungary) multimodal in vivo imaging systems. To detect dynamics and localization of microglia activation we used a micro dose partial inverse BZD agonist ( 125-I - Iomazenil). The change of the general metabolic state in the CNS was monitored by 18-F-FDG PET. 99m-Tc-HMPAO (hexamethylpropylene-amino-oxime) was used for the detection of altered regional cerebral perfusion. The segmentation of different mouse regions was first based on MRI measurements of the animals and for aims of standardization coregistered with an MRI atlas. Results: FDG uptake was increased by systemic LPS in every region of the brain (p<5%). HMPAO uptake was decreased in several brain regions (p<5%). We found that the activity concentration of 125-I-Iomazenil was increased in the hippocampus and cerebellum but not in the cortex after systemic induction of neuroinflammation. Conclusions: FDG uptake increase indicates an increased metabolic rate due to induced brain inflammation. HMPAO uptake change could show glutathione depletion generated decrease of HMPAO fixation induced by reactive oxygen species (ROS) generated by activated inflammatory cells. The surprising result of selective Iomazenil uptake increase could be attributed to a higher amount of an activated but already resident microglia cell pool in the hippocampus as an early step of acute systemic inflammation in the brain. Based on our results the LPS induced changes in the BZD system should be further monitored in neuroinflammation in concordance with ROS status and the time course of the inflammatory changes in this general neuroinflammatory model in mice. A multi-modal imaging approach combining detailed structural and functional approaches elucidates important unknown details of neuroinflammation monitoring. This work was supported in part by INMiND (HEALTH.2011.2.2.1-2 No.278850) of FP7.