Unlike most other organs in your body, the brain is shielded from immune cells circulating in the blood, protecting it from potentially harmful immune responses. However, that is not to say that immune cells are completely absent from the brain; in fact, cells called macrophages migrate to the brain very early on during fetal development and play a crucial role in its proper development and functioning.
While studying the proteins expressed on the surface of brain macrophages in mice, Florent Ginhoux, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), and colleagues quickly realized that there were two distinct populations of macrophages resident in the brain: cells called microglia found in the brain itself, and border-associated macrophages (BAMs) found peripherally in the membrane surrounding the brain.
“People tend to think that all brain macrophages are the same,” said Ginhoux, who collaborated on this study with Melanie Greter at the University of Zurich, Switzerland. “But recent studies have revealed that different types of macrophages reside in parts of the brain, surrounded by different types of cells that can confer completely different functions.”
Although microglia are relatively well-studied and have been linked to several diseases, much less is known about BAMs as they were previously assumed to be the same as microglia.
Using flow cytometry and single-cell transcriptomics to investigate these cells in greater detail, Ginhoux and colleagues identified markers that revealed an early bifurcation in the development of brain macrophages: microglia require TGF-β for development, while BAMs do not.
They also traced the origins of both cell types back to the yolk sac, suggesting that they diverge from each other early during development. “While we showed in 2010 that microglia arise from the yolk sac, we always thought—perhaps naively—that BAMs would come after,” he said. “We were surprised to find that the BAM lineage is also decided very early on, even before the brain itself is fully formed.”
Since microglia are thought to be more involved in brain development while BAMs are believed to perform more of an immune function, having a way to identify the cells could help us understand diseases such as Alzheimer’s and complications related to Zika fetal infection during pregnancy, which have been linked to inflammation in the brain, Ginhoux added.
“The next exciting thing we would like to work on is establishing what are the cues that make these cells adopt one fate versus another in humans,” he said. For that, Ginhoux says he would need to develop an in vitro model, such as a 3D brain organoid model from induced pluripotent stem cells.