Macrophages – the most versatile and multipurpose cells of the immune system – scavenge away pathogens and sick cells to protect us from diseases. We have previously mentioned how macrophages also happen to be present in almost every tissue to perform this very function. Most of the immune cells continuously circulate in the blood, but in a time of need, reach the site of infection/damage as soon as possible. Have you ever imagined what would have happened if the circulating immune cells could not migrate to your fresh wound when you got hurt? It would have taken no time for the infection to get spread throughout the body. Hence, without a doubt, motility is an important aspect of immune cells. From extensive studies, we know that immune cells squeeze through vessel walls (diapedesis) and travel towards the site, attracted by chemokine gradients, a process termed chemotaxis. In most studies, an assumption has been considered that the cell junctions are loose enough for the immune cells to make their way through.
In a study published in Science, Akhmanova and colleagues show how cell division makes way for macrophages to traverse through a densely packed region of the drosophila embryo. Drosophila melanogaster or the fruit fly is a common model organism largely used in the fields of genetics, neuroscience, and developmental biology. Drosophila eggs have been used to understand cellular and molecular development from a single cell into a full-fledged fly for decades.
In this research, macrophage motility was studied in the germband region of an early stage (5-8 hours after fertilization), developing embryo. Macrophages from the head traverse through the germband based on chemical cues, entering the germband at the junction of ectoderm and mesoderm layers. Ectoderm and mesoderm are two of the three primary layers in the embryo that eventually give rise to all other organs and tissues: the ectoderm is the outermost layer that forms external structures including skin and hair follicles; the mesoderm is the middle layer and is responsible for giving rise to most organ systems including circulatory and reproductive. In the germband, the ectoderm and mesoderm are separated by a very thin layer of extracellular matrix (ECM).
Using live imaging, Akhmanova and colleagues observed that macrophages entered this junction of ectoderm and mesoderm at very specific points on each side of the symmetrical hindgut. At these entry points, macrophages entered systematically, one after the other. Most interestingly, they observed that macrophages entered only when the ectodermal cells at the entry point were undergoing mitosis. These normally polygonal cells turned circular during entry, and after some time, doubled and regained their original shapes. Moreover, the division of ectodermal cells at the entry point on either side of the hindgut happened one at a time (asynchronously). Specifically, macrophages entered the side where division happened first, followed by the other side.
To further solidify the macrophage entry during cell division hypothesis, the researchers recorded observations while stopping the ectodermal division using genetic and pharmacological methods. As expected, when the division didn’t occur, almost negligible number of macrophages could cross into the germband. Conversely, knocking out negative regulators (or upregulating positive regulators) of ectodermal cells mitosis led to a higher number of circular cells, and subsequently higher macrophage infiltration compared to normal tissues.
The final question remained, how do macrophages and circular-dividing cells coordinate? The answer was found in the focal adhesion proteins (integrins) – just like a dance, the secret is in “the perfect timing”. Through these integrins, ectodermal cells are attached to the ECM which keeps them anchored and tightly bound. But during mitosis, when these cells circularize, the integrins keep diminishing until for a short time, when they completely disappear. This is the exact time point when macrophages squeeze through the entry point and into the germband. In case you were wondering – yes – the integrins appear again, once the daughter cells gain their normal, polygonal morphology.
Using imaging and other clever strategies, Akhmanova and the group uncovered how ongoing cell division is indirectly making up space, and by temporarily removing the adhesion junctions, giving macrophages a chance to infiltrate the region. The association of cell division and motility of immune cells when explored in complex microenvironments like that in cancer and inflammatory diseases could help us understand them better and also give rise to newer ways of treating them.
Akhmanova M, Emtenani S, Krueger D, Gyoergy A, Guarda M, Vlasov M, Vlasov F, Akopian A, Ratheesh A, De Renzis S, Siekhaus DE. Cell division in tissues enables macrophage infiltration. Science. 2022 Apr 22;376(6591):394-396. doi: 10.1126/science.abj0425.
Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “A Way Through the Crowd: Motility of macrophages in a dense microenvironment”.Tweet