Mast cells, known for their role in allergic reactions, have long been considered key players in our immune system. When they come into contact with allergens, they release chemicals that trigger typical allergic symptoms such as tissue swelling and inflammation. Now, researchers at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the University of Münster have discovered a hidden talent of mast cells: they can capture and use another type of immune cell, neutrophils. This surprising discovery sheds new light on the functioning of our immune system, particularly during allergic reactions.
Inflammation is the body’s response to noxious stimuli, characterized by heat, pain, redness, swelling, and loss of tissue function. When balanced, inflammation protects the body by removing harmful agents and initiating tissue repair. However, excessive inflammation can lead to tissue destruction and disease. The key players in this process are several immune cells, which work together during inflammation. The type of immune cells involved often varies depending on the noxious stimulus, influencing the outcome of the inflammatory response.
Capture of immune cells during allergic responses
Mast cells, which reside in tissues and are instrumental in initiating inflammation, are filled with granules containing pro-inflammatory substances. These granules are released upon contact with potential hazards, including allergens, triggering allergic reactions. In many people, mast cells also react to seemingly harmless environmental factors, which then act as allergens and cause allergies. The interaction between mast cells and other immune cells at the sites of allergic responses has been largely unexplored.
A research group at the Polytechnic Institute of Immunobiology and Epigenetics used a special microscope to visualise the real-time dynamics of activated mast cells and other cell types during allergic reactions in living mouse tissue. Led by Tim Lämmermann, since October 2023 director of the Institute of Medical Biochemistry at the University of Münster, the team discovered a surprising interaction: neutrophils were found inside mast cells. “We couldn’t believe our eyes: there were live neutrophils inside living mast cells. This phenomenon was completely unexpected and would probably not have been discovered in experiments outside a living organism and highlights the power of intravital microscopy,” says Tim Lämmermann.
Using a trick to catch neutrophils
Neutrophils are the front-line defenders of our immune system, responding rapidly and comprehensively to potential threats. They circulate in the blood and rapidly exit blood vessels at sites of inflammation. They are well equipped to combat invaders, such as bacteria or fungi, by engulfing them, releasing antimicrobial substances, or forming net-like traps known as “neutrophil extracellular traps.” In addition, neutrophils can communicate with each other and form swarms of cells to combine their individual functions for the protection of healthy tissue. While much is known about the role of neutrophils in infections and sterile injury, their role in inflammation caused by allergic reactions is less understood.
“It soon became clear that the double accumulation of immune cells was not a mere coincidence. We wanted to understand how mast cells entrap their colleagues and why they do so,” explains Michael Mihlan, first author and co-author of the study published in the journal Cell. Once the team was able to mimic the trapping of neutrophils observed in living tissue in a cell culture, we were able to identify the molecular pathways involved in this process. The researchers discovered that mast cells release leukotriene B4, a substance that neutrophils typically use to initiate their own swarming behavior. By secreting this substance, mast cells attract neutrophils. Once neutrophils are close enough, mast cells engulf them in a vacuole, forming a cell-within-a-cell structure that researchers call the “intracellular mast cell trap” (MIT). “It is ironic that neutrophils, which create net-like traps made of DNA and histones to capture microbes during infections, are now trapped by mast cells in allergic conditions,” says Tim Lämmermann.
Recycled neutrophils to enhance mast cell function
With the help of an international team, the researchers confirmed the formation of MIT in human samples and investigated the fate of the two cell types involved after capture. They found that the trapped neutrophils eventually die and their remains are stored within mast cells. “This is where the story takes an unexpected turn. Mast cells can recycle neutrophil material to power their own function and metabolism. Furthermore, mast cells can release the newly acquired neutrophil components in a delayed manner, triggering additional immune responses and helping to maintain inflammation and immune defense,” says Michael Mihlan.
“This new understanding of how mast cells and neutrophils work together adds a new layer to our knowledge of allergic reactions and inflammation. It shows that mast cells can use neutrophils to boost their own capabilities – an aspect that could have implications for chronic allergic diseases where inflammation occurs repeatedly,” says Tim Lämmermann. The researchers have already started to investigate this interaction in mast cell-mediated inflammatory diseases in humans, exploring whether this discovery could lead to new approaches for the treatment of allergies and inflammatory diseases.