Dysregulation of microglial apoptosis alters their density and the response to systemic inflammation Katharine Askew*1, V. Hugh Perry1, Mark S. Cragg2 and Diego Gomez-Nicola1 1Biological Sciences, University of Southampton, UK; 2Faculty of Medicine, University of Southampton, UK
Microglia, the brain's resident immune cells, have many functions ranging from control of inflammation in brain disease to monitoring synaptic activity. In the healthy murine brain, microglial cell density remains constant throughout life due to a fine balance of coupled proliferation and apoptosis (Askew et al., 2017). It remains unclear how dysregulation of microglial population dynamics may affect microglial function and brain physiology.
In order to study this, we utilised the Vav-Bcl2 transgenic mouse (Egle et al., 2004) as a model of dysregulated microglial apoptosis. These mice have a complete block of intrinsic apoptosis in cells of the myeloid lineage, including microglia, due to overexpression of human Bcl2 under the Vav promoter. They have significantly increased microglial cell density throughout the brain, which peaks at postnatal day (P)44 and is maintained throughout adulthood. Expression of the hBcl2 transgene peaks at P14 but is sustained at a lower level during adulthood.
In particular, elevated numbers of the CD11b+CD45hi subset of microglia contribute to the increase in cell density, suggestive of an altered functional state in the brain compared to wild-type controls. Transcriptomic analysis of isolated microglia revealed differential expression of genes involved in metabolic processes, macromolecule biosynthesis and immune response, indicating that dysregulation of microglial apoptosis changes their phenotype. This altered phenotype elicits an exacerbated pro-inflammatory response in the brain of Vav-Bcl2 mice after systemic challenge with LPS. Further investigation of the inflammatory response to LPS in vitro will inform as to whether this exacerbated response is simply a consequence of elevated cell density.
Our data suggests that long-term deregulation of apoptosis in microglia results in significant phenotypic changes, altering their functional response to LPS-mediated inflammation. Dysregulation of microglial population dynamics throughout lifetime may have implications for the onset and progression of age-related neurological diseases.
Credits: None available.
You must be logged in and own this product in order to post comments.