Cell division clears the way for immune cells

fly larva

Drosophila larvae with macrophages migrating through the tissue (purple) © Maria Akhmanova

A study shows that when a cell divides, its connections to neighboring cells loosen. It is precisely then that the first immune cell pushes itself into the resulting gap and paves the way for itself and the subsequent immune cells. If, on the other hand, cell division is stopped with medication, the immune cells cannot reach the corresponding 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 place of use, they penetrate tiny pores and make paths through the extracellular matrix that surrounds the cells. So far, however, it was still unknown how exactly they manage to penetrate tissue made up of cells that are densely packed.

Macrophages on the move

A team led by Maria Akhmanova from the Institute of Science and Technology Austria (ISTA) has now solved this puzzle. To do this, the researchers used a high-performance microscope to track how the macrophages in larvae of the fruit fly Drosophila spread during embryonic development. In Drosophila, macrophages are among the most common immune cells. Since the fruit fly larvae are almost transparent, the migration of the scavenger cells can be observed particularly well on them.

During early embryonic development, the immune cells, guided by chemical signals, make their way to their target tissues, in this case the so-called germ line of the larvae. Here they encounter a kind of wall of densely packed cells. “The first macrophage needs about 20 minutes to overcome the tissue barrier,” the researchers report. In doing so, it pushes itself between the tissue cells with the cell nucleus first. The other macrophages follow the first, the so-called pioneer cell, in a chain on the same path.

Only the division of tissue cells (green) enables the macrophages (purple) to penetrate the tissue. © Maria Akhmanova/ ISTA

penetration at the right moment

To understand the exact mechanism, Akhmanova and her colleagues analyzed numerous time-lapse videos of the macrophage invasion. “We found that the entry of the macrophages always takes place at a point in time when the tissue cell divides before the pioneer macrophage,” they report. “If the intrusion occurred at a random time, at least half the time it would fall into a non-dividing phase. However, that was never the case.”

The scientists tested this observation by specifically switching off cell division with the help of drugs. And indeed: Without dividing cells as a portal of entry, the macrophages could not get into the tissue. On the other hand, if the team increased the cell division rate, the macrophages could penetrate the tissue more quickly. But what exactly during cell division enables the immune cells to migrate? Is it the fact that the cell becomes round just before it divides, creating a slightly larger space between it and the neighboring cells? Or the fact that certain molecules that anchor the cell to its environment become detached during cell division?

Loose connections crucial

In order to find out, the researchers first ensured that the tissue cells in question could become round, but did not loosen their connections to their surroundings. The result: although new spaces were created by the rounding of the cell, these were too small for scavenger cells to migrate. “The rounding alone is not sufficient to enable the macrophages to migrate,” the researchers conclude. In the next step, they manipulated the connecting molecules between the tissue cells in such a way that they held the cells together less strongly, even outside the cell division phase. Under these conditions, the macrophages could easily migrate into the tissue. The rounding that occurs during division was not necessary for this.

“Although we cannot rule out that other effects may also contribute, this result demonstrates that the dissolution of connections between a cell and its environment is the most important mechanism by which cell division opens the door for macrophage migration,” they write Akhmanova and her team. From her point of view, the new findings 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

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