Many people consult their friends and neighbors before making a big decision. It turns out that cells also are consulting their neighbors in the human body.
Scientists and physicians have long known that immune cells migrate to the site of an infection, which individuals experience as inflammation -- swelling, redness and pain. Now, researchers have uncovered new evidence that this gathering is not just a consequence of immune activation. Immune cells count their neighbors before deciding whether or not the immune system should kick into high gear.
Understanding how to influence inflammation and activate an immune response could lead to new therapies to treat chronic autoimmune diseases or to mobilize the immune system to help fight cancer.
"This is a previously unrecognized aspect of immune function," said the co-lead of the study. "The cells make a coordinated decision. They don't uniformly activate but instead collectively decide how many cells will activate, so that together, the system can fend off a threat without dangerously overreacting."
"A key part of this work relied on the development of new computational models to interpret our experiments and elucidate how cells perform calculations to make coherent decisions," said the other co-lead. The research is published in the journal Nature Communications.
"It's especially interesting because the immune system is decentralized," the author said. "Immune cells are individual agents that need to work together, and nature has come up with a solution for how they can get on the same page. Cells arrive at different activation states, but in such a way that, on the whole, the population response is calibrated."
To explore this phenomenon, the researchers examined macrophages, a type of immune cell that is part of the first line of defense for combatting infection and disease. They observed how macrophages responded to a chemical produced by bacteria -- a red flag that alerts the body to the presence of infection -- using techniques that enabled the researchers to watch individual cells' responses over time. They then used computational models to help interpret and explain these observations.
The authors show that bimodal phenotypic partitioning of macrophages is primed during the resting state, dependent on cumulative history of cell density, predicted by extrinsic noise in transcription factor expression, and independent of canonical LPS-induced intercellular feedback in the tumor necrosis factor (TNF) response. The analysis shows how this density-dependent coupling produces a nonlinear effect on collective TNF production.
"Over time, the cells observe their surroundings to get a sense of their neighbors," the author said. "Each cell becomes poised to respond as a high activator or not. Now that we know there's this additional layer controlling the immune system, it opens up a whole avenue to study whether there are new targets for immunomodulation."
The researchers believe this information could be used to help design better drugs as well as to guide the engineering of advanced cell-based therapies.
"Biology has evolved so many fascinating and surprising ways to control complex processes," the co-lead said. "As synthetic biologists, we work to engineer cells to perform customized therapeutic functions, such as activating the immune system locally at a tumor site but not throughout the patient. Understanding nature's innovations helps us to come up with new designs and enables us to be better engineers."
https://news.northwestern.edu/stories/2020/02/immune-cells-consult-with-neighbors-to-make-decisions/
https://www.nature.com/articles/s41467-020-14547-y
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmacrophages-employ&filter=22
Macrophages consult with neighbors to make decisions
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