Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have discovered a specialized population of neutrophils in the skin that produce extracellular matrix components, helping to maintain the skin’s integrity and resistance to microorganisms. Findings from the study, in mice, indicate that the immune system not only targets pathogens, but also physically strengthens the skin to prevent them from entering the body.
The discovery broadens understanding of the immune system and may lead to new strategies for treating skin diseases, inflammation, diabetes, and age-related conditions. “These findings will help develop treatments to strengthen the skin barrier in patients with inflammatory diseases or immunological alterations, including patients with diabetes and older adults,” suggested research lead Andrés Hidalgo, PhD.
The researchers reported on their findings in Nature. In the paper, titled “Matrix-producing neutrophils populate and shield the skin,” they wrote, “We conclude that the innate immune system has evolved strategies to physically shield the organism from external challenges, even before they occur.”
Organisms are protected from the outside world by dedicated barriers, among which the skin provides the main physical protection not only against mechanical injuries but also from the microbial ecosystems of the outer skin, the authors explained. “If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells.”
Neutrophils are an important type of circulating immune cell, and while these cells are best known for their microbicidal properties, the new study reveals an unexpected role for neutrophils in the generation and remodeling of the subepidermal extracellular matrix. “The extracellular matrix is critical for maintaining the structure and function of the skin and other tissues, acting as a barrier to the entry of microorganisms and toxins,” Hidalgo explained.
The study found that the newly identified specialized neutrophils populate the skin, where they produce collagen and other matrix proteins that strengthen the skin barrier. “In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties, and promote barrier function,” the team stated. “After injury, these neutrophils build ‘rings’ of matrix around wounds, which shield against foreign molecules and bacteria.”
The study findings also showed that this structural function of skin neutrophils is regulated by the TGF-β signaling pathway. When the investigators genetically deleted this pathway in mice, the deposition of the extracellular matrix was diminished, resulting in skin that was more fragile and permeable. “This structural program relies on TGFβ signaling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion,” the scientists wrote.
First author Tommaso Vicanolo, PhD, further commented that the study “… demonstrates that these neutrophils help to maintain skin integrity under normal conditions and are activated in response to injury to generate protective structures around wounds that prevent the entry of bacteria and toxins.” Hidalgo added that the findings suggest that “… the interaction between the immune system and the body’s structural components is much more direct than previously believed.”
Representative photo showing how neutrophils (in green) surround the wound and produce a collagen ring (in red) that prevents the entry of pathogens or toxins. [CNIC]
Representative photo showing how neutrophils (in green) surround the wound and produce a collagen ring (in red) that prevents the entry of pathogens or toxins. [CNIC]
Another result emerging from the study is that the activity of these skin neutrophils follows a day-night pattern, adjusting the production of extracellular matrix according to the body’s circadian cycle. As a result, the skin of mice is more resistant at night than during the day, due to the nocturnal peak in neutrophil activity. “This finding opens new avenues for investigating how internal body rhythms influence tissue defense, regeneration, and repair,” Hidalgo suggested.
For Hidalgo, now at Yale University School of Medicine, the discovery of extracellular matrix-producing neutrophils not only broadens knowledge about innate immunity but also suggests new treatment strategies for skin diseases and immunological disorders.
The authors concluded that their work—the result of a collaboration between various CNIC groups and laboratories in Germany, the United States, Singapore, and China, “signals a change in the way we view the immune system’s protective role in the body.” Hidalgo is currently investigating the possible implications of the study findings for fibrotic processes and cancer.