Scientists at CNIC have identified a specialized group of neutrophils in the skin that produce extracellular matrix. This activity helps reinforce the skin’s barrier and enhances its ability to defend against infection.
A team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), led by Dr. Andrés Hidalgo, has discovered a specialized group of neutrophils in the skin that produce extracellular matrix. This process helps maintain the skin’s strength and integrity. Published in Nature, the study shows that the immune system not only defends against pathogens but also physically strengthens the skin to prevent their entry into the body.
Neutrophils are a key type of immune cell in circulation. The specialized neutrophils found in this study reside in the skin, where they produce collagen and other matrix proteins that reinforce the skin barrier. This discovery expands our understanding of the immune system and could lead to new treatment strategies for skin diseases, inflammation, diabetes, and age-related conditions.
While neutrophils are widely known for their ability to fight infections, this study reveals their unexpected role in generating and remodeling the subepidermal extracellular matrix. Hidalgo explains, “The extracellular matrix is essential for maintaining the structure and function of the skin and other tissues, acting as a barrier against microorganisms and toxins.”
First author Tommaso Vicanolo adds 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.”
TGF-β Pathway Regulates Structural Function
The study further shows that this structural function of skin neutrophils is regulated by the TGF-β signaling pathway. By genetically deleting this pathway in mice, the authors showed that the deposition of the extracellular matrix was diminished, resulting in skin that was more fragile and permeable. Hidalgo notes, “This suggests that the interaction between the immune system and the body’s structural components is much more direct than previously believed.”
Another fascinating 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, thanks to the nocturnal peak in neutrophil activity. Hidalgo underlines that, “This finding opens new avenues for investigating how internal body rhythms influence tissue defense, regeneration and repair.”
Implications for Treatment of Skin Disorders
For Hidalgo, now at Yale University School of Medicine, the discovery of matrix-producing neutrophils not only broadens knowledge about innate immunity but also suggests new treatment strategies for skin diseases and immunological disorders. He explains, “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.”
The authors conclude that this advance—the fruit of 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.”
Dr. Hidalgo is currently investigating the possible implications of the study findings for fibrotic processes and cancer.
Reference: “Matrix-producing neutrophils populate and shield the skin” by Tommaso Vicanolo, Alaz Özcan, Jackson LiangYao Li, Carla Huerta-López, Iván Ballesteros, Andrea Rubio-Ponce, Andra C. Dumitru, Jose Ángel Nicolás-Ávila, Miguel Molina-Moreno, Pablo Reyes-Gutierrez, Andrew D. Johnston, Catherine Martone, Eric Greto, Antonio Quílez-Alvarez, Enrique Calvo, Elena Bonzon-Kulichenko, Rebeca Álvarez-Velez, Ming Yao Chooi, Immanuel Kwok, Blanca González-Bermúdez, Benoit Malleret, Francisco M. Espinosa, Ming Zhang, Yu-Long Wang, Dasheng Sun, Shu Zhen Chong, Ali El-Armouche, Kevin K. Kim, Irina A. Udalova, Valentina Greco, Ricardo Garcia, Jesús Vázquez, Ana Dopazo, Gustavo R. Plaza, Jorge Alegre-Cebollada, Stefan Uderhardt, Lai Guan Ng and Andrés Hidalgo, 19 March 2025, Nature.
DOI: 10.1038/s41586-025-08741-5
The study was supported by funding from Fundación “la Caixa”, the Boehringer Ingelheim Foundation, the National Institutes of Health, and the Swiss National Science Foundation.
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