Prior Replacement of Microglia Reduces Brain Injury and Inflammation Following Hemorrhagic Stroke
Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Like macrophages, microglia are involved in tissue maintenance and repair, as well as in clearance of molecular waste and destruction of pathogens. Interestingly, microglia are one of the classes of immune cell that, similarly to B cells, will repopulate quite rapidly following selective destruction. That destruction is now routinely achieved in animal models using small molecule CSF1R inhibitors.
When this destruction and replacement is performed in old animals, the new microglia lack many of the undesirable features characteristic of microglia in old tissues, and behave in a more youthful fashion. Senescent microglia are removed, but there are likely other beneficial differences before and after.
This has attracted some interest in that part of the research community involved in finding ways to address the aging of the brain. As shown in today's open access research, when this microglial replacement is accomplished prior to brain injury, it can reduce the normal, unhelpful, inflammatory reaction to that trauma. Lasting inflammation and disruption of brain tissue function are reduced. This is perhaps a measure of the degree to which aged microglia are biased towards harmful inflammation.
Inflammation is a critical aggravator of neural injury following brain insults. In the aged brain, microglia exhibit an exaggerated and uncontrolled inflammatory phenotype in response to brain insults or immune stimulation. Rather than an enhanced immune response at baseline level, aged microglia possess a primed profile that is demonstrated by augmented production of inflammatory factors such as interleukin (IL)-1β and reactive oxygen species following stimulus. Although evidence suggests a link between the primed profile of the aged microglia and vulnerability of the old brain to inflammation-related secondary injury following acute insult, it remains poorly understood to what extent the aged microglia with a primed profile can impact the neuroinflammation and the outcome of acute brain injury.
The survival of microglia critically depends on signaling through the colony-stimulating factor 1 receptor (CSF1R). Administration of CSF1R inhibitor PLX3397 eliminates microglia in the whole brain that continues when CSF1R inhibition is present. Moreover, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, leading to effective replacement of the entire microglia population, a process takes approximately 2-3 weeks to complete.
Recent evidence suggests that withdrawal of CSF1R inhibitors in the old mice leads to complete repopulation of new microglia with characteristics resembling young microglia. Therefore, withdrawal of CSF1R inhibitors in the old brain resets the primed microglia and provides an opportunity to determine the impact of aged microglia on neural injury upon brain insults. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection.
We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α, and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.