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Immune Cell Hunting Start-Stop System

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How immune cells coordinate their swarming behavior to effectively kill pathogens: a publication in “Science” presents new findings.

The body is well protected against invading pathogens by barriers such as the skin. But if you injure yourself and break your skin, pathogens can easily enter your body through the wound and cause serious infections. If this happens, the innate immune system takes over the first rapid defense with an effective arsenal of cellular weapons infiltrating injured tissue in large numbers.

As one of the first types of cells on site, neutrophilic granulocytes are recruited within hours from the bloodstream to the site of infection to eliminate potential microbial invaders.

Neutrophils are very abundant cells that make up about 50-70% of the white blood cells in the human body. It is estimated that 100 billion neutrophils are produced every day from stem cells in the bone marrow of an adult.

Swarming against infections

“Neutrophils are very effective in chasing and killing bacteria,” explains Tim Lämmermann. The MPI group leader for immunobiology and epigenetics in Friborg is studying this important cell type.

“These cells patrol almost every corner of our body and they are very good at detecting anything that could be harmful in our body. Once individual neutrophils detect damaged cells or invading microbes in the tissue, they begin to secrete attractive signals that act through cell surface receptors on nearby neutrophils to recruit more and more cells.

Using this intercellular communication, neutrophils can act together as a cellular collective and effectively coordinate their elimination of pathogens as a swarm.

A fine line between host protection and tissue destruction

However, this beneficial form of inflammation can also overtake and lead to massive tissue damage. If the intensity or duration of the response becomes deregulated, the same mechanisms that serve to eliminate invading pathogens can also cause collateral damage to healthy tissue. For example, substances that neutrophils release to kill invading pathogens also erode the protein and sugar mesh, which provides structural support to tissues.

“In this study, we started with the question of what stops the swarming response to prevent the uncontrolled build-up of neutrophils and prevent excessive inflammation, which can contribute to degenerative diseases such as cancer, diabetes and autoimmune diseases ”, explains Tim Lämmermann.

In previous studies, he and his team have already discovered the molecular mechanisms behind collective-type swarming behavior. However, the processes that terminate this response have remained unknown.

Neutrophil swarming is still a relatively new topic in the fields of inflammation and infection research, and the underlying mechanisms are only just beginning to be studied. The latest study from Tim Lämmermann’s lab now reveals how neutrophils themselves limit their swarming activity in bacteria-infected tissue and thus balance the search and kill phases for effective pathogen removal.

Using specialized microscopy for real-time visualization of immune cell dynamics in living mouse tissues, researchers demonstrate that swarming neutrophils become unresponsive to their own secreted signals that triggered the swarm in the first place.

“We have identified a molecular disruption in neutrophils that stops their movement, once they detect high concentrations of swarm attractants accumulating in large clusters of neutrophils,” explains Tim Lämmermann.

“This was surprising because the dominant opinion suggested that the external signals released by the tissue environment or directly by pathogens are essential for stopping the activity of neutrophils in the resolving phase of inflammation,” comments Wolfgang Kastenmüller , collaborating scientist in the Max Planck research group in systems immunology. at Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.

An internal start-stop system for optimal bacterial elimination

In light of the start-stop system discovered in neutrophils, the researchers reassessed current views on how neutrophils navigate tissues to effectively kill bacteria.

In experiments with neutrophils lacking a shutdown mechanism, the team observed immune cells overgrowth and sweeping across large areas of bacteria-infected tissue, which contrasted the behavior of cells with the start-stop system. functional.

However, this amplified swarming and sweeping did not make these cells better pathogen killers.

“Surprisingly, we did the opposite. It is not beneficial when the neutrophils move too fast and run like crazy. Instead, it seems more beneficial for them to stop and enjoy a good meal of bacteria together – it’s more effective at containing bacterial growth in tissue, ”explains Tim Lämmermann.

With these results, the team paves the way for a better understanding of neutrophil biology, which is essential for the host’s immune defense against bacteria and could inform therapeutic approaches in the future. Additionally, swarming behavior and underlying mechanisms could also inform other categories of collective behavior and self-organization in cells and insects.

Publication

Neutrophil swarming is self-limiting to contain bacterial growth in vivo. Kienle K, Glaser KM, Eickhoff S, Mihlan, M, Knöpper K, Réategui E, Epple MW, Gunzer M, Baumeister R, Tarrant TK, Germain RN, Irimia D, Kastenmüller, W, Lämmermann T (2021). In: Science 372, DOI: 10.1126 / science.abe7729