Depleting microglia from a juvenile brain: consequences for irradiation-induced neuroinflammation M Havermans1, K Zhou1, S Goto1, K Blomgren1 1Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
Microglia, the brain's immune cells, are extremely important in the brain's response to noxious stimuli like irradiation (IR) used in cranial radiotherapy (CRT) (1). CRT, often being part of brain tumor treatment, is effective in treating tumors, but if typically leaves brain tumor survivors with cognitive deficits, including problems with memory and learning, later in life (2). Depletion of microglia from the brain is followed by repopulation in which new microglia are being formed, presumably from blood-derived monocytes. These “new microglia” have been shown to have anti-inflammatory effects compared to their predecessors (3). The aim of our study was to examine the effect of microglia depletion on irradiation-induced neuroinflammation in the juvenile brain.
We used CX3CR1CreER/+R26DTA/+ double-transgenic mice to specifically eliminate CX3CR1-expressing microglia via diphtheria toxin expression in these cells upon tamoxifen injection. With this method, we reached a 97% decrease in microglia levels throughout the brain during the first week after injection. Irradiating the brain within this time-window resulted in a stronger caspase3 activity and more cell death in the subgranular zone of the hippocampus 24 but not 6 hours after IR. This could be a result of delayed cell death and/or an impaired phagocytosis capacity of the microglia depleted brain tissue. CCL2 production at these time points was elevated dramatically in the microglia depleted mice compared to non-depleted, while irradiation only also increases CCL2 levels, both in microglia-depleted and non-depleted animals. Based on these results, the microglia depletion will be further investigated.
Ten days after injection, the brain is repopulated with total microglia numbers being 20% higher than controls. Approximately 90% of these microglia are blood-derived and their morphology was very different from microglia in control brains, displaying fewer and thicker processes. These microglia are possibly similar to microglia in early stages, when microglia initially populate the brain. This will be further investigated in future experiments as well as the effects of irradiation of the brain in these repopulating stages.
References 1. Lee SW, Haditsch U, Cord BJ, Guzman R, Kim SJ, Boettcher C, et al. Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation. Brain, behavior, and immunity. 2013;30:33-44. 2. Peris-Bonet R, Martinez-Garcia C, Lacour B, Petrovich S, Giner-Ripoll B, Navajas A, et al. Childhood central nervous system tumours--incidence and survival in Europe (1978-1997): report from Automated Childhood Cancer Information System project. European journal of cancer (Oxford, England : 1990). 2006;42(13):2064-80. 3. Han J, Harris RA, Zhang X-M. An updated assessment of microglia depletion: current concepts and future directions. Molecular Brain. 2017;10:25.
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