How do immune cells enter tissues to protect the body?
Immune cells can move within our body, even between firmly attached cells. How do they overcome these impediments? Studying fruit fly embryos, we have discovered that immune cells take advantage of dividing cells. Because intercellular attachments disassemble during division, it creates a weak spot in the dense tissue, through which immune cells can migrate.
Most cells in our body don’t move: they stay put, forming dense tissues. But one population of cells moves continually, and we would not survive without them. These immune cells arrive at any spot in our body where damage or infection arises. Immune cells can crawl through compact material, get in and out of blood vessels, and squeeze between densely packed cells in tissues. Although Elie Metchnikoff discovered their movement towards infection and wounds 140 years ago, we still have a limited understanding of how they overcome the challenges they face inside our bodies.
To shed light on how immune cells do this in real live tissues, we investigated cell invasion inside fruit fly embryos. These tiny transparent eggs allow us to image cellular behavior under the microscope while the embryo develops. Although fruit flies are evolutionarily far from humans, their immune cells are remarkably similar to ours. Studying these cells in this simple organism lets us identify principles relevant to human health.
Macrophages, a type of immune cells, provide the first defense against infection by engulfing pathogens. They also act as garbage collectors by swallowing and digesting dead cells at a wound or early in embryonic development when many cells die. Macrophages also secrete biomolecules which anchor tissues, called extracellular matrix, and thus regulate organs’ development. For these purposes, macrophages invade tissues and spread around the entire fly embryo.
Entering a tissue is a stumbling block for macrophages: they stop for many minutes at the edge. But what do they do there? Accumulate energy or activate its migratory mechanisms? Previous studies showed that they do all that ahead of time to prepare for entry, but still have to wait for something else before they can invade.
To find out what else could be going on, we imaged the invasion site very closely. Unexpectedly, we discovered that macrophages wait for a cell at the tissue edge to divide! Once this cell rounds up as it starts to divide, macrophages squeeze beside it into the tissue. This division appears to be essential. When we blocked divisions completely, no macrophages invaded. The opposite experiment, increasing the division rate of surrounding cells, accelerated invasion.
But why does division enable macrophage invasion? We first tested if the round shape of a dividing cell is crucial, potentially by opening up space around itself; that could allow the macrophage to insert into the tissue more easily. We therefore induced cell rounding in the absence of division by artificially increasing contraction at the cell edge. However, this procedure did not accelerate macrophage penetration.
We then tested a second hypothesis. During division, a cell loses its connections to neighboring cells. Indeed, we observed that the adhesion proteins which attach the tissue cells to their surrounding disassemble during division, just before macrophage invasion. Reducing the amount of these adhesion proteins resulted in the much easier invasion of macrophages and an invasion which no longer depended on division. Thus, disassembly of the cell-cell connections is what macrophages are waiting for to start invasion! A dividing cell acts like the opening of a gate through which macrophages can sneak past a brick wall.
Our finding shows that the behavior of the surroundings is as important in controlling the journey of immune cells as the properties of the migrating cells themselves. This provides a new perspective on how we can try to combat diseases of the immune system and even cancer. Cancer cells can become migratory, invading other tissues and forming new tumors called metastases. Anti-division drugs that inhibit tumor growth might also act against metastases by decreasing the division of tissues so that tumor cells cannot move into them. Such drugs could also restrain the overactivity of the immune system.
On the other hand, decreasing cell attachment might help immune cells to enter tissues and fight infections. Having “a key to the gate” could allow us to stop or stimulate cell invasion depending on what is needed. We hope that future research will result in new treatments based on this idea.
Akhmanova, M., Emtenani, S., Krueger, D., Gyoergy, A., Guarda, M., Vlasov, M., Vlasov, F., Akopian, A., Ratheesh, A., de Renzis, S., & Siekhaus, D. E. (2022). Cell division in tissues enables macrophage infiltration. Science, 376(6591), 394–396. https://doi.org/10.1126/science.abj0425