The study shows that when a cell divides, its connections to neighboring cells loosen. It is then that the first immune cell squeezes into the gap and paves the way for itself and other immune cells. If, on the other hand, cell division is stopped with drugs, the immune cells cannot reach the appropriate tissue.
As part of the innate immune system, macrophages, a subset of white blood cells, patrol the body. As scavenger cells, they eliminate pathogens by absorbing and destroying them. On their way to the site of application, they penetrate fine pores and create pathways through the extracellular matrix surrounding cells. Until now, however, it was not known how exactly they managed to penetrate the tissue made of densely packed cells.
A team led by Maria Akhmanova from the Austrian Institute of Science and Technology (ISTA) has solved this puzzle. To this end, scientists used a high-throughput microscope to track the spread of macrophages in Drosophila larvae during embryonic development. In Drosophila, macrophages are among the most common immune cells. As the larvae of fruit flies are almost transparent, the migration of scavenger cells can be observed especially well.
In the early stages of embryonic development, immune cells, guided by chemical signals, penetrate the target tissues, in this case the so-called the germ line of the larvae. Here they encounter a kind of wall of densely packed cells. “The first macrophage takes about 20 minutes to cross the tissue barrier,” the researchers say. In this way, it pushes between the cells of the tissue, first the cell nucleus. Other macrophages follow the first, so-called pioneer cell, in a chain along the same path.
penetration at the right moment
To understand the exact mechanism, Akhmanova and her colleagues analyzed numerous time-lapse videos of macrophage invasions. “We found that macrophage entry always takes place when a tissue cell divides before a pioneering macrophage,” they report. “If the intrusion had happened at a random time, at least half of the time it would have fallen into the Sunday phase. But that never happened. “
The researchers tested this observation by turning off the cells from dividing with drugs. Indeed: without cell division as a portal of entry, macrophages would not be able to enter the tissue. On the other hand, if the team increased the rate of cell division, macrophages could penetrate the tissue faster. But what exactly during cell division enables immune cells to migrate? Is it a fact that a cell becomes round just before it divides, creating a slightly larger space between it and neighboring cells? Or the fact that certain molecules that anchor a cell to its environment break off during cell division?
Loose key connections
To find out, scientists first made sure that the cells of the tissue in question could turn round, but they did not loosen their connections with the environment. Result: Although new gaps were formed as a result of cell rounding, they were too small for the scavenger cells to migrate. ‘Rounding alone is not enough to allow macrophages to migrate,’ the researchers conclude. In the next step, they manipulated the molecules that connect tissue cells in such a way that they hold the cells together less tightly, even outside the cell division phase. Under these conditions, macrophages can easily migrate into the tissue. The rounding that occurs during the division was not necessary for this.
“While we cannot exclude that other effects may also contribute to this, this result shows that the breakdown of connections between a cell and its environment is the most important mechanism by which cell division opens the door to macrophage migration,” write Akhmanova and her team . . From her point of view, the new discoveries could also contribute to a better understanding of cancer and autoimmune diseases in the future.
Source: Maria Akhmanova (Institute of Science and Technology Austria, ISTA) et al., Science, doi: 10.1126 / science.abj0425