Neutrophils, the most abundant immune cells in our bodies, are known for their destructive roles: killing pathogens, clearing out infections, and, sometimes to our detriment, wreaking havoc on surrounding tissues in the process. But now, scientists at Yale School of Medicine (YSM) have discovered a new role for neutrophils, one that involves the building and maintenance of healthy skin.
Their study was published in Nature on March 19.
These cells are still neutrophils by the textbook, but they become functionally something else. What is the more appropriate definition of a cell? Is it what it looks like or what it does?
Andrés Hidalgo, PhD
“Neutrophils are always thought of as cells that help you get over an infection and are present in an inflammation setting,” says Alaz Ozcan, PhD, postdoctoral associate at YSM and one of the lead authors of the study. “We found that’s not the only case. They exist in healthy tissues and also participate in keeping those tissues intact.”
Ozcan and the research team, a group that includes a large number of collaborators from institutions across six different countries, found that in mice, neutrophils not only populate healthy, uninfected skin, but also release “extracellular matrix,” the network of proteins and molecules that surround and provide structure outside of cells. By depositing extracellular matrix proteins such as collagen and fibronectin, neutrophils reinforce the structure and integrity of the skin. Until now, scientists thought this task was relegated to fibroblasts, the most abundant cells in connective tissue.
“Neutrophils are a bit like a jack of all trades,” says Andrés Hidalgo, PhD, professor of immunobiology at YSM and one of the principal investigators of the study. “They’re really good at taking on new tasks, and in the skin, that trade is building matrix.”
Neutrophils populate our bodies in a circadian pattern. During periods of rest, neutrophil numbers are very low throughout the body. During waking hours, those numbers increase, and neutrophils circulate to different tissues.
Through experiments led by co-lead author Tommaso Vicanolo, a PhD student at the Spanish National Center for Cardiovascular Research, the researchers found that changes in mouse skin coincided with these circadian patterns: skin stiffness almost doubled from night to day.
“It follows the same pattern of neutrophil infiltration of the skin, so the skin stiffness increases when the mice are ready to start their day and goes down when they’re resting,” says Hidalgo, who is also a member of Yale Cancer Center. “It’s very bizarre.”
Hidalgo speculates that there may be an evolutionary advantage to this circadian skin stiffness, that tougher skin during waking and hunting hours could confer an advantage. And while these findings were in mice, he expects that the same phenomenon would occur in humans, especially given that human neutrophils also follow a circadian pattern. Notably, the researchers found evidence of neutrophils producing extracellular matrix in human tissue samples, which again emphasizes the likelihood that these findings apply across species.
“From what we’ve seen so far, humans resemble mice in this effect of neutrophils on skin integrity,” Hidalgo says.
Given the potential translatability of these findings, the study holds valuable clinical implications. For one, skin with high structural integrity, as reinforced by neutrophils, provides the body with a physical barrier to prevent pathogen entry. Without that structural support from neutrophils, there’s a greater chance of infection.
“In the absence of matrix produced by neutrophils, the skin tissue will lose its stiffness, so it basically becomes looser, and it becomes more permeable, which means that it has more potential to let in foreign substances,” says Ozcan.
Importantly, the researchers also discovered that neutrophils play a role in preventing microbial entry into wounds. After creating a small puncture in the ears of the mice, the team found that neutrophils were producing extracellular matrix proteins that helped create a barrier to prevent microbes and toxins from entering the wound.
For immunocompromised individuals with low levels of neutrophils, this poses a number of problems.
“Having a reduced immune defense might not only compromise how you respond to the pathogen, but the wounds that are formed in the skin could also take longer to heal because the cells that produce matrix are the same immune cells that are failing,” Hidalgo says.
Hidalgo sees potential in a therapeutic strategy that capitalizes on the ability of neutrophils to take on new roles, but more than anything, these findings suggest we need a different way of thinking about our immune cells.
“These cells are still neutrophils by the textbook, but they become functionally something else,” he says. “What is the more appropriate definition of a cell? Is it what it looks like or what it does? This is a bit of a revolution in biology and immunology, that cells can be doing many more things than they were assigned.”
Above all, Hidalgo is left with one undeniable conclusion from this work: “Neutrophils are awesome.”
The research reported in this news article was supported in part by the National Institute of Allergy and Infectious Diseases (award R01AI165661) and the National Heart, Lung, and Blood Institute (awards NHLBI R01HL156998 and NHLBI R01HL153056). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.